Opioid compounds

ABSTRACT

Diarylmethyl piperazine compounds having utility as exogenous receptor combinant species for binding with receptors such as delta, mu, sigma, and/or kappa receptors are disclosed. Compounds of the invention may be employed as conjugates in agonist/antagonist pairs for transductional monitoring and assays of neurotransmitter function, and also variously exhibit therapeutic utility, including mediating analgesia, and possessing utility for the treatment of diarrhea, urinary incontinence, mental illness, drug and alcohol addiction/overdose, lung edema, depression, asthma, emphysema, cough, and apnea, respiratory depression, cognitive disorders, emesis and gastrointestinal disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 08/169,879, filed Dec. 17, 1993 now abandoned, which in turn isa continuation-in-part of U.S. patent application Ser. No. 08/098,333,filed Jul. 30, 1993 now abandoned, which in turn is acontinuation-in-part of International Patent Application No.PCT/GB93/00216, filed Feb. 2, 1993, now published as WO93/15062, anddesignating therein the United States as a Designated State, all ofwhich are incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates generally to diarylmethyl piperazine compoundshaving utility in medical therapy especially as receptor-bindingspecies, e.g., as conjugates in agonist/antagonist pairs forverifying/assaying receptor and neurotransmitter function. The compoundsof the invention are useful as opioid receptor compounds having utilityin treatment of pain, combatting drug addiction, alcohol addiction, drugoverdose, mental illness, urinary incontinence, cough, lung edema,emesis, diarrhea, depression, and cognitive, respiratory, andgastro-intestinal disorders. The invention also relates topharmaceutical formulations of such compounds, methods of treatingcertain disorders with such compounds, and processes by which suchcompounds may be prepared.

2. Description of the Related Art

In the study of opioid biochemistry, a variety of endogenous opioidcompounds and non-endogenous opioid compounds has been identified. Inthis effort, significant research has been focused on understanding themechanism of opioid drug action, particularly as it relates to cellularand differentiated tissue opiate receptors.

Opioid drugs typically are classified by their binding selectivity inrespect of the cellular and differentiated tissue receptors to which aspecific drug species binds as a ligand. These receptors include mu (μ),delta (δ), sigma (σ) and kappa (κ) receptors.

The well-known narcotic opiates, such as morphine and its analogs, areselective for the opiate mu receptor. Mu receptors mediate analgesia,respiratory depression, and inhibition of gastrointestinal transit.Kappa receptors mediate analgesia and sedation. Sigma receptors mediatevarious biological activities.

The existence of the opioid delta receptor is a relatively recentdiscovery which followed the isolation and characterization ofendogenous enkephalin peptides which are ligands for the delta receptor.Research in the past decade has produced significant information aboutthe delta receptor, but a clear picture of its function has not yetemerged. Delta receptors mediate analgesia, but do not appear to inhibitintestinal transit in the manner characteristic of mu receptors.

Opioid agents frequently are characterized as either agonists orantagonists. Agonists and antagonists are agents which recognize andbind to receptors, affecting (either initiating or blocking)biochemical/physiological sequences, a process known as transduction.Agonists inhibit or suppress neurotransmitter outputs in tissuescontaining receptors, e.g., inhibiting pain responses, or affectingother output-related phenomena. Antagonists also bind to receptors, butdo not inhibit neurotransmitter outputs. Thus, antagonists bind to thereceptor sites and block the binding of agonist species which areselective for the same receptor.

Concerning specific receptor ligands, the distinction between deltareceptor agonists and antagonists heretofore has been made by theiractivity in the electrically stimulated mouse vas deferens assay, whichtypically has been considered the appropriate diagnostic tissue for thedelta receptor. By contrast, mu receptor agonists are generallycharacterized by their activity in the electrically stimulated guineapig ileum assay.

Only a relatively small number of essentially pure deltareceptor-selective agents is known, and with the exception of the deltaopioid receptor antagonists disclosed in Portoghese U.S. Pat. No.4,816,586, all known delta receptor-selective opioid compounds arepeptides, including endogenous enkephalins and other endorphins, as wellas exogenous peptide analogs. The previously synthesized exogenouspeptide analogs have various associated disadvantages in terms of theirstability, their potentially suitable delivery mutes as administereddrug agents, and their in vivo tissue distribution.

Various physiological effects of the known peptide-based opioid ligandshave been studied, including: analgesia; respiratory depression;gastrointestinal effects; mental, emotional, and cognitive processfunction; and mediation/modulation of other physiological processes.

The aforementioned U.S. Pat. No. 4,816,586, issued Mar. 28, 1989 to P.S. Portoghese, discloses various delta-opioid receptor antagonists ofspecified formula. The disclosed antagonist compounds are formed byfusion of an indole, benzofuran, benzopyrazine, or quinoline ringsystem, to the C-ring of naltrexone. These compounds are described aspossessing a unique opioid receptor antagonist profile, includingcompounds which are highly selective for the delta opioid receptor.

U.S. Pat. No. 4,518,711 issued May 21, 1985 to V. J. Hruby et al.describes cyclic, conformationally constrained analogs of enkephalins.These compounds include both agonists and antagonists for the deltareceptor.

In addition to the above-described references relating to opioidcompounds, the art relevant to the compounds of the present inventionincludes the polyaryl piperazine compounds described in the variousreferences identified below.

S. Goenechea, et al., in "Investigation of the Biotransformation ofMeclozine in the Human Body," J. Clin. Chem. Clin. Biochem., 1988,26(2), 105-15, describe the oral administration of a polyaryl piperazinecompound in a study of meclozine metabolization in human subjects.

In "Plasma Levels, Biotransformation and Excretion of Oxatomide in Rats,Dogs, and Man," Meuldermans, W., et al., Xenobiotica, 1984, 15(6),445-62, there is disclosed a metabolic study of plasma levels,biotransformation, and excretion of oxatomide.

T. Iwamoto, et al., in "Effects of KB-2796, A New Calcium Antagonist,and Other Diphenylpiperazines on ³ H!nitrendipine Binding," Jpn. J.Pharmacol., 1988, 48(2), 241-7, describes the effect of a polyarylpiperazine of specified formula, as a calcium antagonist.

K. Natsuka, et al., in "Synthesis and Structure-Activity Relationshipsof 1-Substituted 4-(1,2-Diphenylethyl)piperazine Derivatives HavingNarcotic Agonist and Antagonist Activity," J. Med. Chem., 1987, 30 (10),1779-1787, disclose racemates and enantiomers of 1-substituted 4-2-(3-hydroxyphenyl)-1-phenylethyl!piperazine derivatives.

European Patent Application No. 458,160 published 27 Nov. 1991 describessubstituted diphenylmethane derivatives which are said to be useful asanalgesic and antiinflammatory agents, including compounds wherein themethylene bridging group (linking the two phenyl moieties) may have as asubstituent on the methylene carbon a piperidinyl or piperazinyl group.

South African Patent Application No. 8604522 published 17 Dec. 1986discloses N-substituted arylalkyl and aryl-alkylene substitutedamino-heterocyclic compounds, including piperidine derivatives, whichare described as useful cardiovascular, antihistamine, andanti-secretory agents.

European Patent Application No. 133,323 published 20 Feb. 1985 disclosescertain diphenylmethyl piperazine compounds useful as non-sedativeantihistamines.

There is a continuing need in the art for improved opioid compounds,particularly compounds which are free of adverse side effects ofconventional opiates such as morphine and pethidine.

SUMMARY OF THE INVENTION

The present invention relates to diarylmethyl piperazine compounds ofthe formula: ##STR1## wherein: R⁸ and R⁹ may be the same or different,and may be hydrogen, C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, C₅ -C₁₀ aryl, orC₅ -C₁₀ arylC₁ -C₆ alkyl, or R⁸ and R⁹ together may form a ring of 5 or6 atoms;

R³, R⁴, R⁵ =hydrogen or methyl, where the total number of methyl groupsis one or two; and

R⁶ =hydrogen, C₁ -C₆ alkyl, C₂ -C₆ methoxyalkyl, or C₃ -C₆ cycloalkyl,

or a pharmaceutically acceptable ether, ester, salt, or otherphysiologically functional derivative thereof.

The compounds of the invention have opioid receptor binding activity andhave utility in medical therapy, in particular for the treatment ofpain.

DETAILED DESCRIPTION OF THE INVENTION, AND PREFERRED EMBODIMENTS THEREOF

As used herein, in reference to the present invention, the term "alkyl"is intended to be broadly construed as encompassing: (i) alkyl groups ofstraight-chain as well as branched chain character; (ii) unsubstitutedas well as substituted alkyl groups, wherein the substituents ofsubstituted alkyl groups may include any sterically acceptablesubstituents which are compatible with such alkyl groups and which donot preclude the efficacy of the diarylmethyl piperazine compound forits intended utility (examples of substituents for substituted alkylgroups include halogen (e.g., fluoro, chloro, bromo, and iodo), amino,amido, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, nitro, hydroxy, etc.); (iii)saturated alkyl groups as well as unsaturated alkyl groups, the latterincluding groups such as alkenyl-substituted alkyl groups (e.g., allyl,methallyl, propallyl, butenylmethyl, etc.), alkynyl-substituted alkylgroups, and any other alkyl groups containing sterically acceptableunsaturation which is compatible with such alkyl groups and which doesnot preclude the efficacy of the diarylmethyl piperazine compound forits intended utility; and (iv) alkyl groups including linking or bridgemoieties, e.g., heteroatoms such as nitrogen, oxygen, sulfur, etc.

As used herein, in reference to the present invention, the term "aryl"is intended to be broadly construed as referring to carbocyclic (e.g.,phenyl, naphthyl) as well as heterocyclic aromatic groups (e.g.,pyridyl, thienyl, furanyl, etc.) and encompassing unsubstituted as wellas substituted aryl groups, wherein the substituents of substituted arylgroups may include any sterically acceptable substituents which arecompatible with such aryl groups and which do not preclude the efficacyof the diarylmethyl piperazine compound for its intended utility.Examples of substituents for substituted aryl groups include one or moreof halogen (e.g., fluoro, chloro, bromo, and iodo), amino, amido, C₁ -C₄alkyl, C₁ -C₄ alkoxy, nitro, trifluoromethyl, hydroxy, hydroxyalkylcontaining a C₁ -C₄ alkyl moiety, etc.

By "physiologically functional derivative" is meant a pharmaceuticallyacceptable salt, ether, ester or salt of an ether or ester of thecompound of formula (I) or any other compound which, upon administrationto the recipient, is capable of providing (directly or indirectly) thesaid compound of formula (I) or an active metabolite or residue thereof.Phenolic C₁ -C₆ alkyl ethers are a sub-class of physiologicallyfunctional derivatives of the compounds of formula (I).

In enantiomeric forms, compounds of the invention include individualenantiomers of the compounds of formula (I) in single species formsubstantially free of the corresponding enantiomer, as well as inadmixture (in mixtures of enantiomeric pairs and/or in mixtures ofmultiple enantiomer species).

A sub-class of compounds within the scope of formula (I) are thepharmaceutically acceptable esters and salts thereof.

Examples of pharmaceutically acceptable esters of the invention includecarboxylic acid esters of hydroxy groups in compounds of formula (I) inwhich the non-carbonyl moiety of the carboxylic acid portion of theester grouping is selected from straight or branched chain alkyl (e.g.n-propyl, t-butyl, n-butyl), alkoxyalkyl (e.g. methoxymethyl), arylalkyl(e.g. benzyl), aryloxyalky (e.g. phenoxymethyl), and aryl (e.g. phenyl);alkyl-, aryl-, or arylalkylsulfonyl (e.g. methanesulfonyl); amino acidesters (e.g. L-valyl or L-isoleucyl); dicarboxylic acid esters (e.g.hemisuccinate); carbonate esters (e.g. ethoxycarbonyl); carbamate esters(e.g. dimethylaminocarbonyl, (2-aminoethyl)aminocarbonyl); and inorganicesters (e.g. mono-, di- or triphosphate).

Examples of pharmaceutically acceptable salts of the compounds offormula (I) and physiologically functional derivatives thereof includesalts derived from an appropriate base, such as an alkali metal (forexample, sodium, potassium), an alkaline earth metal (for example,calcium, magnesium), ammonium and NX₄ ⁺ (wherein X is C₁ -C₄ alkyl).Pharmaceutically acceptable salts of an amino group include salts of:organic carboxylic acids such as acetic, lactic, tartaric, malic,lactobionic, fumaric, and succinic acids; organic sulfonic acids such asmethanesulfonic, ethanesulfonic, isethionic, benzenesulfonic andp-toluenesulfonic acids; and inorganic acids such as hydrochloric,hydrobromic, sulfuric, phosphoric and sulfamic acids. Pharmaceuticallyacceptable salts of a compound having a hydroxy group consist of theanion of said compound in combination with a suitable cation such asNa⁺, NH₄ ⁺, or NX₄ ⁺ (wherein X is for example a C₁₋₄ alkyl group).

For therapeutic use, salts of compounds of formula (I) will bepharmaceutically acceptable, i.e., they will be salts derived from apharmaceutically acceptable acid or base. However, salts of acids orbases which are not pharmaceutically acceptable may also find use, forexample, in the preparation or purification of a pharmaceuticallyacceptable compound. All salts, whether or not derived from apharmaceutically acceptable acid or base, are within the scope of thepresent invention.

A sub-class of compounds within the scope of formula (I) are compoundswherein R⁶ is C₁ -C₆ alkyl or C₃ -C₆ cycloalkyl.

A sub-class of compounds within the scope of formula (I) are compoundswherein R³ and R⁵ are both methyl and R⁴ is hydrogen.

A sub-class of compounds within the scope of formula (I) are compoundswherein one of R⁸ and R⁹ is phenyl optionally substituted with one ormore substituents selected from the group consisting of halogen, C₁ -C₃alkoxy and trifluoromethyl.

Preferably, halogen is chloro or fluoro and C₁ -C₃ alkoxy is methoxy.

A preferred sub-class of compounds of the above formula (I) includethose in which the moiety NR⁸ R⁹ is selected from the group consistingof: ##STR2##

Another preferred sub-class of compounds within the scope of the presentinvention comprises compounds of the formula: ##STR3## wherein: R⁸ andR⁹ may be the same or different, and may be hydrogen, C₁ -C₆ alkyl, C₃-C₆ cycloalkyl, C₅ -C₁₀ aryl, or R⁸ and R⁹ together may form a ring of 5or 6 atoms,

or a pharmaceutically acceptable ether, ester, salt, or otherphysiologically functional derivative thereof.

A further preferred sub-class of compounds within the scope of thepresent invention comprises compounds of formula (II) wherein one of R⁸and R⁹ is phenyl optionally substituted with one or more substituentsselected from the group consisting of halogen, C₁ -C₃ alkoxy, C₁ -C₃alkyl and trifluoromethyl, and the other of R⁸ and R⁹ is hydrogen orsaturated C₁ -C₆ hydrocarbyl or unsaturated C₃ -C₆ hydrocarbyl, or apharmaceutically acceptable ether, ester, salt, or other physiologicallyfunctional derivative thereof.

As used herein, in reference to the present invention, the term"hydrocarbyl" is intended to encompass a group containing only carbonand hydrogen atoms which may contain double or triple bonds and whichmay be cyclic or aromatic in nature.

Illustrative compounds of the invention include the compounds identifiedbelow.

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-fluorophenyl)-N-methylbenzamide

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-phenylbenzamide

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-chlorophenyl)-N-methylbenzamide

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-phenylbenzamide

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-(2-pyridyl)benzamide

(-)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-phenylbenzamide

3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-(2-(trifluoromethyl)phenyl)benzamide

3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-(2,4,6-trichlorophenyl)benzamide

3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-(4-pyridyl)benzamide

3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-(3-pyridyl)benzamide

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-benzyl-N-methylbenzamide

(±)-cis-3-(α-(4-Allyl-3,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

3-((αR orαS)-α-((2S,5S)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

3-((αR orαS)-α-((2R,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-phenethylbenzamide

3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-isopropyl-N-methylbenzamide

(-)-3-((αR)-α-((2S,5R)-4-(Cyclopropylmethyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

(+)-3-((αR)-α-((2S,5R)-2,5-Dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

(+)-3-((αR)-α-((2S,5R)-2,5-Dimethyl-4-ethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

(-)-3-((αR)-α-((2S,5R)-2,5-Dimethyl-4-(2-propynyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

(±)-3-((αR*)-α-((2S*,5R*)-2,5-Dimethyl-4-propyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

(+)-3-((αR)-α-((2S,5R)-2,4,5-Trimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-phenyl-N-propylbenzamide

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-methoxyphenyl)-N-methylbenzamide

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(2-fluorophenyl)-N-methylbenzamide

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-(2-fluorophenyl)benzamide

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-allyl-N-phenylbenzamide

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(cyclopropyl)methyl-N-phenylbenzamide

3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-isopropyl-N-phenylbenzamide

3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-cyclopropyl-N-phenylbenzamide

3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-propylbenzamide

3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-(3-fluorophenyl)benzamide

3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(2-fluorophenyl)-N-propylbenzamide

3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-(2-fluorophenyl)benzamide

3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-methoxyphenyl)-N-propylbenzamide

3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-(4-methoxyphenyl)benzamide

(+)-3-((αS)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-phenylbenzamide

(+)-3-((αR)-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide

(+)-3-((αR)-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N-ethyl-N-(4-fluorophenyl)benzamide

3-((R)-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-(N-(3-fluorophenyl)-N-methylcarbamoyl)benzyl)phenylmonophosphate,

and pharmaceutically acceptable salts thereof.

Compounds of the above general formula (I) exhibit binding selectivityfor receptor(s). Depending on the structure and stereo-specificity ofthe particular formula (I) compounds, such compounds may exhibit bindingability to receptor(s) selected from the group consisting of deltareceptors, mu receptors, kappa receptors, sigma receptors, andcombinations of such receptors.

Various compounds within general formula (I) exhibit delta receptoragonist activity including mediating analgesia. Other compounds of suchgeneral formula exhibit delta receptor antagonist activity, ashereinafter more fully described. Still other compounds within thegeneral formula exhibit mu receptor activity, and more particularly, insome instances, mixed mu receptor/delta receptor activity.

Compounds of the above general formula (I) and the illustrativecompounds listed in the preceding paragraph have utility as exogenousreceptor combinant compounds, i.e., compounds useful for binding with anopioid receptor. The combinant compound may be a conjugate in anagonist/antagonist pair which may be employed for transductional assayof neurotransmitter function in appertaining cellular or differentiatedtissue systems. In addition to receptor assay, differential binding, andspecificity applications for cellular, histological, and corporealmonitoring and assessment purposes, the compounds of the above generalformula (I) variously exhibit specific bioactivity characteristicsrendering them useful as treatment agents for various physiological andpathological conditions.

The compounds of the above general formula (I) include agonist speciesuseful for the treatment of pain, diarrhea, depression, urinaryincontinence, mental illness, cough, lung edema, respiratory depression,gastrointestinal disorders, spinal injury, and drug addiction.

The compounds of the above general formula (I) also include antagonistspecies which as mentioned are useful as agonist conjugates forneurotransmitter assay applications as well as antagonist species withutility for treatment of emesis, alcohol abuse, and drug overdose ofopiate or other agonist species.

In addition, to the extent that degeneration or dysfunction of opioidreceptors is present or implicated in a disease state involving tissueor discrete cellular loci, isotopically labeled versions of opioidcompounds of the present invention find utility in diagnostic andimaging applications, e.g., diagnostic techniques involving positronemission tomography (PET) scans of the brain.

As mentioned hereinabove, opioid receptor sites are loci on cells whichrecognize and bind opiate and opioid drugs, which in turn can affect(initiate/block) biochemical/physiological sequences (transduction).

In the case of the non-peptide opioid agents contemplated by the presentinvention, the structure/activity pattern for the various compoundswithin the general formula (I) is highly diverse, and subtle differencessuch as changes in stereochemistry can result in differenttransductional effects. Thus, formula (I) comprehends agonist species aswell as antagonist species.

In the case of delta receptor agonists, activity is generallydistinguished and measured by activity in the electrically stimulatedmouse vas deferens assay. Further, empirical determinations utilizingcompounds of the present invention provide strong evidence of theexistence of a delta receptor subtype in the brain that is differentfrom the delta receptor in the mouse vas deferens.

In consequence of the existence of such delta receptor subtypes, otherreceptor binding assays or screening techniques, e.g., analgesiascreening tests, may be employed as a further predictor of agonist orantagonist activity for specific compounds of the present invention.

In the case of mu receptor agonists, activity is generally distinguishedand measured by activity in the electrically stimulated guinea pig ileumassay.

Particular preferred compounds from the above-listed illustrativecompounds of the invention include

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-fluorophenyl)-N-methylbenzamide

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-phenylbenzamide

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-phenylbenzamide

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-phenyl-N-propylbenzamide

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-methoxyphenyl)-N-methylbenzamide

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(2-fluorophenyl)-N-methylbenzamide

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-(4-fluorophenyl)benzamide,

and pharmaceutically acceptable salts thereof.

Table I below shows the chemical structure of the nine above-identifiedparticularly preferred compounds of the present invention, denotedherein as compounds "A", "B", "C", "D", "E", "F", "G", "H", and "I",respectively.

                  TABLE I                                                         ______________________________________                                         ##STR4##                                                                      ##STR5##                                                                      ##STR6##                                                                      ##STR7##                                                                      ##STR8##                                                                      ##STR9##                                                                      ##STR10##                                                                     ##STR11##                                                                     ##STR12##                                                                    ______________________________________                                    

These compounds A, B, C, D, E, F, G, H and I are highly selective opioidreceptor ligand species. All are efficacious in mediating analgesia. Ingeneral, the spectrum of analgesic utilities of diarylmethyl piperazinecompounds of the invention may be readily determined without undueexperimentation by simple receptor binding screening tests. In thisrespect, and merely by way of illustration, the diarylmethyl piperazinecompounds of the invention which are predominantly mu receptor agonistsmay be utilized for example in mediating surgical analgesia.Diarylmethyl piperazine compounds of the invention which arepredominantly delta receptor agonists may be utilized for example inmediating epidural analgesia. Diarylmethyl piperazine compounds of theinvention which are mixed mu/delta opioid agonists, e.g., Compounds A,B, C, D, E, F, G, H, and I, may be utilized for example in mediatingsurgical and/or post-operative analgesia.

The mixed mu/delta receptor character of various compounds within thescope of the present invention entails a substantial advantage overvarious known mu receptor compounds currently employed as analgesics.

The vast majority of currently used high potency analgesics, includingmorphine, fentanyl, meperidine, sufentanil, and codeine, are mu receptorbinding compounds. As is well established, these compounds, while highlyefficacious for mediating analgesia, have accompanying side effects,including disorientation, attenuation of mental acuity, muscle rigidity,and respiratory depression, and withdrawal side-effects includingnausea, vomiting, shakes, seizures, and sweats. Such side effects aretypically absent or at least much reduced in use of analgesia-mediatingdelta receptor binding species. Accordingly, the use of mixed mu/deltareceptor species of the present invention may attenuate or eveneliminate the side effects normally attendant the use of mu receptorbinding compounds.

The compounds of the invention when used in pharmaceutical or diagnosticapplications desirably are prepared in substantially pure enantiomerform, with an enantiopurity of at least 90% enantiomeric excess (EE),preferably at least 95% EE, more preferably at least 98% EE, and mostpreferably at least 99% EE. Enantiomeric excess values provide aquantitative measure of the excess of the percentage amount of a majorisomer over the percentage amount of a minor isomer which is presenttherewith, and may be readily determined by suitable methods well-knownand established in the art, as for example chiral high pressure liquidchromatography (HPLC), chiral gas chromatography (GC), nuclear magneticresonance (NMR) using chiral shift reagents, etc.

Compounds A, B, C, D, E, F, G, H, and I are enantiomerically pureanalgesic agents exhibiting agonism at both mu and delta opioidreceptors. In rodent test subjects, for example, these compounds produceanalgesia comparable to mu-analgesic morphine, but produce a muchreduced extent of muscle rigidity and respiratory depression. Further,rodent tests show these compounds to be free of proconvulsant activity,such as may be associated with structurally related pure delta agonists.

Although it might be assumed at first impression that all delta agonistcompounds of the present invention would have similar in vivo profiles,with potencies parallel to mouse vas deferens activity, this is notinvariably the case.

The diarylmethyl piperazine compounds of the invention include compoundswhich have significant potency in the receptor binding assay (ratbrain), compounds that are predominantly active at one or the other ofthe delta receptor subtypes, and compounds having mu receptor activityor mixed mu receptor/delta receptor activity.

Binding assay and analgesia test results show that compounds of thepresent invention variously mediate analgesia in respect of a widevariety of stimuli and physiological perturbations. This in turnevidences a high level of complexity in neurotransmitter functions andstimulus-related responses associated with various opioid receptors,including mu receptors, delta receptors, delta receptor sub-types andkappa receptors.

A number of compounds of the present invention within formula (I), ortheir chemical precursors (which also in many instances constitute novelcompounds and thus are contemplated within the scope of the presentinvention), evidence biological activities in addition to opioidactivity, e.g., biological activity including sigma receptor bindingaffinity, and multidrug resistance activity.

As is apparent from the foregoing discussion, the compounds of thepresent invention have broad utility in the treatment of a wide varietyof physiological conditions and disorders. The invention accordinglycontemplates the use of such compounds in the manufacture of amedicament for the treatment or prophylaxis of such physiologicalconditions and disorders. In addition to those treatment applicationsalready mentioned, other utilities for compounds of the presentinvention include the treatment of bronchial disorders such as asthma,emphysema, and apnea.

Further, endogenous opioids such as enkephalins and endorphins, andtheir neurological systems, have been identified in connection withvarious CNS disorders, such as compulsive behavior, depression,psychosis, etc., and agonist or antagonist species within formula (I) ofthe present invention have utility in combatting such disorders.

Various agonist species as well as antagonist species of the compoundsof formula (I) also find utility in the treatment of drug(opioid/narcotic) abuse/addiction, and thus have utility for replacementof methadone or other conventional opiate agents in drug rehabilitationprograms, to the extent that conventional drug treatment agents haveside effects or other disadvantages which contraindicate or limit theiruse.

Concerning drug addiction treatment with effective compounds within thebroad scope of the present invention, it is noted that methadone is amu-receptor opiate with actions similar to morphine, i.e., methadone isabusable and addictive. Methadone is used as a "maintenance therapy"agent for opiate addicts, so that such individuals can remain functionalwhile satisfying their addictions in a safer and non-criminal manner. Inthis respect, compounds of the invention may have utility in place of,or as an adjunct to, currently used treatments for drug addiction, suchas those involving naltrexone, methadone, clonidine, etc.

Certain compounds within the scope of the present invention, asdiscussed above, have utility in effecting local analgesia, such asspinal analgesia, and compounds of the invention may also find utilityin appetite suppression applications, and the like.

Compounds of the present invention include various compounds which aredelta-opioid agonists in the mouse vas deferens delta receptor subtype,as well as compounds which are antagonists at such delta receptorsubtype. The compounds of the present invention also include compoundswhich are agonists or antagonists at the delta receptor in the brain,which appears, on the basis of empirical determinations, to be adifferent delta receptor subtype than the delta receptor in the mousevas deferens. A substantial number of compounds of the aforementionedgeneral formula (I) of the invention have either agonist or antagonistactivity at both delta receptor subtypes. A number of these compoundshave high activity at the mu-opioid receptor, either as pure mu receptorbinding compounds or as mixed mu receptor/delta receptor bindingcompounds, and still other compounds within the broad scope of thepresent invention have significant affinity for the sigma receptor.

In in vitro tests for agonist/antagonist activity, such as receptorbinding affinity tests, and inhibition of electrically stimulated muscletwitch tests, compounds of the present invention exhibit potency over arange of from nanomolar to micromolar concentrations, depending on thespecific compound employed.

Compounds of the present invention have pharmaceutical activity,including, inter alia, analgesic activity, and are useful in treatinganimals, e.g., mammals such as humans, for conditions in which analgesiais desired.

A method of treating pain in an animal in need of such treatmentcomprises administering to the animal an effective analgesia-inducingamount of a compound of formula (I).

In addition, various compounds of the present invention havingappertaining therapeutic utility may be usefully employed in thetreatment of conditions including: drug and alcohol addiction/overdose;mental, emotional, and cognitive disorders; cough; lung edema; emesis;respiratory depression; and gastrointestinal disorders. Correspondingly,the present invention contemplates a method of treating an animalsubject having such condition(s) and in need of such treatment,comprising administering to such animal an effective amount of acompound of the present invention which is therapeutically effective forsaid condition.

Subjects to be treated by the methods of the present invention includeboth human and non-human animal (e.g., bird, dog, cat, cow, horse)subjects, and are preferably mammalian subjects, and most preferablyhuman subjects.

Depending on the specific condition to be treated, animal subjects maybe administered compounds of formula (I) at any suitable therapeuticallyeffective and safe dosage, as may readily be determined within the skillof the art, and without undue experimentation.

In general, while the effective dosage of compounds of the invention fortherapeutic use may be widely varied in the broad practice of theinvention, depending on the specific application, condition, or diseasestate involved, as readily determinable within the skill of the art,suitable therapeutic doses of the formula (I) compounds, for each of theappertaining compositions described herein, and for achievement oftherapeutic benefit in treatment of each of the conditions describedherein, will be in the range of 1 microgram (μg) to 100 milligrams (mg)per kilogram body weight of the recipient per day, preferably in therange of 5 μg to 75 mg per kilogram body weight per day, and mostpreferably in the range of 10 μg to 50 mg per kilogram body weight perday. The desired dose is preferably presented as two, three, four, five,six, or more sub-doses administered at appropriate intervals throughoutthe day. These sub-doses may be administered in unit dosage forms, forexample, containing from 10 μg to 1000 mg, preferably from 50 μg to 500mg, more preferably from 50 μg to 250 mg, and most preferably from 50 μgto 10 mg of active ingredient per unit dosage form. Alternatively, ifthe condition of the recipient so requires, the doses may beadministered as a continuous infusion.

The mode of administration and dosage forms will of course affect thetherapeutic amounts of the compounds which are desirable and efficaciousfor the given treatment application.

For example, orally administered dosages typically are at least twice,e.g., 2-10 times, the dosage levels used in parenteral administrationmethods, for the same active ingredient. In oral administration forinducing analgesia, dosage levels for mu and/or mixed delta/mu receptorbinding compounds of the invention may be on the order of 5-200 mg/70 kgbody weight/day. Intrathecal administration dosage levels generally areon the order of about 10% of the levels characteristic of parenteraladministration dosage levels. In tablet dosage forms, typical activeagent dose levels suitable for inducing analgesia are on the order of10-100 mg per tablet.

The compounds of formula (I) may be administered per se as well as inthe form of pharmaceutically acceptable ethers, esters, salts, and otherphysiologically functional derivatives thereof.

The present invention also contemplates pharmaceutical formulations,both for veterinary and for human medical use, which comprise as theactive agent one or more compound(s) of the invention.

In such pharmaceutical formulations, the active agent preferably isutilized together with one or more pharmaceutically acceptablecarrier(s) therefor and optionally any other therapeutic ingredients.The carrier(s) must be pharmaceutically acceptable in the sense of beingcompatible with the other ingredients of the formulation and not undulydeleterious to the recipient thereof. The active agent is provided in anamount effective to achieve the desired pharmacological effect, asdescribed above, and in a quantity appropriate to achieve the desireddaily dose.

The formulations include those suitable for parenteral as well asnon-parenteral administration, and specific administration modalitiesinclude oral, rectal, topical, nasal, ophthalmic, subcutaneous,intramuscular, intravenous, transdermal, spinal, intrathecal,intra-articular, intra-arterial, sub-arachnoid, bronchial, lymphatic,and intra-uterine administration. Formulations suitable for parenteraladministration are preferred.

When the active agent is utilized in a formulation comprising a liquidsolution, the formulation advantageously may be administeredparenterally. When the active agent is employed in a liquid suspensionformulation or as a powder in a biocompatible carrier formulation, theformulation may be advantageously administered orally, rectally, orbronchially.

When the active agent is utilized directly in the form of a powderedsolid, the active agent may advantageously administered orally.Alternatively, it may be administered bronchially, via nebulization ofthe powder in a carrier gas, to form a gaseous dispersion of the powderwhich is inspired by the patient from a breathing circuit comprising asuitable nebulizer device.

In some applications, it may be advantageous to utilize the active agentin a "vectorized" form, such as by encapsulation of the active agent ina liposome or other encapsulant medium, or by fixation of the activeagent, e.g., by covalent bonding, chelation, or associativecoordination, on a suitable biomolecule, such as those selected fromproteins, lipoproteins, glycoproteins, and polysaccharides.

The formulations comprising the active agent of the present inventionmay conveniently be presented in unit dosage forms and may be preparedby any of the methods well known in the art of pharmacy. Such methodsgenerally include the step of bringing the active compound(s) intoassociation with a carrier which constitutes one or more accessoryingredients. Typically, the formulations are prepared by uniformly andintimately bringing the active compound(s) into association with aliquid carrier, a finely divided solid carrier, or both, and then, ifnecessary, shaping the product into dosage forms of the desiredformulation.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets, tablets,or lozenges, each containing a predetermined amount of the activeingredient as a powder or granules; or a suspension in an aqueous liquoror a non-aqueous liquid, such as a syrup, an elixir, an emulsion, or adraught.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine, with the active compound being in afree-flowing form such as a powder or granules which optionally is mixedwith a binder, disintegrant, lubricant, inert diluent, surface activeagent, or discharging agent. Molded tablets comprised of a mixture ofthe powdered active compound with a suitable carrier may be made bymolding in a suitable machine.

A syrup may be made by adding the active compound to a concentratedaqueous solution of a sugar, for example sucrose, to which may also beadded any accessory ingredient(s). Such accessory ingredient(s) mayinclude flavorings, suitable preservative, agents to retardcrystallization of the sugar, and agents to increase the solubility ofany other ingredient, such as a polyhydroxy alcohol, for exampleglycerol or sorbitol.

Formulations suitable for parenteral administration convenientlycomprise a sterile aqueous preparation of the active compound, whichpreferably is isotonic with the blood of the recipient (e.g.,physiological saline solution). Such formulations may include suspendingagents and thickening agents and liposomes or other microparticulatesystems which are designed to target the compound to blood components orone or more organs. The formulations may be presented in unit-dose ormulti-dose form.

Nasal spray formulations comprise purified aqueous solutions of theactive compounds with preservative agents and isotonic agents. Suchformulations are preferably adjusted to a pH and isotonic statecompatible with the nasal mucous membranes.

Formulations for rectal administration may be presented as a suppositorywith a suitable carrier such as cocoa butter, hydrogenated fats, orhydrogenated fatty carboxylic acids.

Ophthalmic formulations are prepared by a similar method to the nasalspray, except that the pH and isotonic factors are preferably adjustedto match that of the eye.

Topical formulations comprise the active compound dissolved or suspendedin one or more media, such as mineral oil, petroleum, polyhydroxyalcohols, or other bases used for topical pharmaceutical formulations.

Transdermal formulations may be prepared by incorporating the activeagent in a thixotropic or gelatinous carrier such as a cellulosicmedium, e.g., methyl cellulose or hydroxyethyl cellulose, with theresulting formulation then being packed in a transdermal device adaptedto be secured in dermal contact with the skin of a wearer.

In addition to the aforementioned ingredients, formulations of thisinvention may further include one or more accessory ingredient(s)selected from diluents, buffers, flavoring agents, binders,disintegrants, surface active agents, thickeners, lubricants,preservatives (including antioxidants), and the like.

The compounds of formula (I) and pharmaceutically acceptable esters,salts, and other physiologically functional derivatives thereof, may beformed by the exemplary synthetic techniques described in theaforementioned International Patent Application No. WO93/15062, filedFeb. 2, 1993.

The present invention also contemplates a process for the preparation ofa compound of formula (I), as defined hereinabove, or a pharmaceuticallyacceptable ester, ether, salt, or other physiologically functionalderivative thereof, said process comprising a synthesis procedureselected from the group consisting of synthesis procedures (A), (B) and(C) below:

(A) the alkylation of a piperazine of formula (IV) by an alkylatingagent of formula (III), ##STR13## wherein R³ to R⁶ and R⁸ and R⁹ are asdefined in any of the preceding claims, P is hydrogen or anhydroxy-protecting group and X¹ is a leaving group; and, when R⁶ ishydrogen, optionally alkylating the resulting compound of formula (I)with an alkylating agent of the formula R⁶ -X¹, wherein R⁶ is saturatedC₁ -C₆ hydrocarbyl, unsaturated C₃ -C₆ hydrocarbyl or C₂ -C₆methoxyalkyl and X¹ is a leaving group, or optionally alkylating theresulting compound of formula (I) by reductive amination with a C₁ -C₆aldehyde in the presence of a reducing agent;

(B) reacting a compound of formula (V), ##STR14## wherein R³ to R⁶ areas defined above, P is as defined above and Z is bromo, iodo ortrifluoromethylsulfonyl as appropriate, with

(a) in the case where Z is bromo or iodo; an alkyl metal, or suitablyreactive metal, optionally transmetallating the resulting metalliccompound with a transition metal species to provide a different metalliccompound, reacting the resulting metallic compound with carbon dioxideand converting the resulting carboxylic acid to the corresponding acidchloride, anhydride or ester, and reacting the resulting acid chloride,anhydride or ester with an amine of the formula HNR⁸ R⁹ wherein R⁸ andR⁹ are as defined herein or reacting the resulting metallic compoundwith an aminocarbonyl chloride compound of formula CICONR⁸ R⁹, whereinR⁸ and R⁹ are as defined herein; or

(b) in the case where Z is bromo, iodo or trifluoromethylsulfonyl; acyanating reagent, hydrolyzing the resulting nitrile with alkali oraqueous mineral acid, convening the resulting carboxylic acid to thecorresponding acid chloride, anhydride or ester, and reacting theresulting acid chloride, anhydride or ester with an amine of the formulaHNR⁸ R⁹ wherein R⁸ and R⁹ are as defined herein; or

(c) in the case where Z is bromo, iodo or trifluoromethylsulfonyl;excess amine of the formula HNR⁸ R⁹ wherein R⁸ and R⁹ are as definedherein and carbon monoxide in the presence of a transition metalcatalyst to yield a compound of formula (I), wherein R⁸ and R⁹ are asdefined herein; or

(C) reacting a compound of formula (VI), with a phenylmetallic compoundof formula (VII): ##STR15## wherein R³ to R⁶ and R⁸ and R⁹ are asdefined heroin, P is hydrogen or a hydroxy-protecting group, M is ametal species and W is benzotriazolyl or trichlorotitaniumoxy;(Katritzky, A. R.; Yannakopoulou, K.; Lue, P.; Rasala, D.; Urogdi, L;J.Chem. Soc., Perkin Trans. 1, 1139, (1989); Seebach, D.; Betscart, C.;Schiess, M. Helv. Chim. Acta, 67, 1593. (1984)) and, when P is anhydroxy-protecting group, deprotecting the hydroxy group;

optionally converting the resulting compound of formula (I) into apharmaceutically acceptable ether, ester or salt thereof or aphysiologically functional derivative thereof.

Procedure A

The reaction between an alkylating agent of formula (III) and apiperazine of formula (IV) may be carried out in a solvent such astoluene or acetonitrile.

Alkylating agents of the formula R⁶ -X¹ are commercially available ormay be prepared by published procedures. As an alternative to alkylationwith an alkylating agent R⁶ -X¹, the method of reductive amination maybe employed in which an appropriate commercially available C₁ -C₆aldehyde is reduced with a reducing agent such as sodiumcyanoborohydride in solvents such as alcohols or ethers.

Procedure B

(a) A compound of formula (I) may be prepared from a compound of formula(V), wherein Z is bromo or iodo and P is a hydroxy-protecting group,such as tert-butyldimethylsilyl, by low-temperature (e.g. -60° C. to-78° C.) metal exchange of the reactive halogen with an organometallicreagent, such as n-butyllithium, or an activated form of a metal, suchas lithium or magnesium, to provide an intermediate metallic compound,followed by reaction with carbon dioxide to provide the carboxylic acidin an anhydrous solvent such as tetrahydrofuran, under an inertatmosphere (e.g. nitrogen). The carboxylic acid may then be convened tothe carboxamide of formula (I) by the methods described below.

Alternatively, the intermediate metallic compound generated from acompound of formula (V) may be treated with an appropriate carbamoylchloride (ClCONR⁸ R⁹) to produce a compound of formula (I).

(b) A compound of formula (I) may also be prepared from a compound offormula (V) wherein Z is bromo, iodo or triflate(trifluoromethylsulfonyl) by treatment with a cyanating reagent, such ascuprous cyanide, in a suitable solvent such as dimethylformamide orN-methylpyrrolidinone, to provide the corresponding compound of formula(V) wherein Z is nitrile, which may be further hydrolyzed to thecorresponding carboxylic acid with alkali or aqueous mineral acid. Thecarboxylic acid may then be converted to a compound of formula (I) byvarious means known in the art, such as formation of the acid chloride(e.g. with thionyl chloride or oxalyl chloride) or by formation of themixed anhydride (e.g. with isobutyl chloroformate) or by formation of anactivated ester with conventional peptide-coupling reagents (e.g.dicyclohexylcarbodiimide orbenzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate), any of which activated intermediates may beconvened to the desired carboxamide of formula (I) by reaction with anappropriate amine (HNR⁸ R⁹) in a suitable solvent such asdichloromethane or dimethylformamide.

(c) A compound of formula (I) may also be prepared from a compound offormula (V), wherein Z is bromo, iodo or triflate, by treatment with atransition metal catalyst, such astetrakis(triphenylphosphine)palladium, in the presence of excess amineand carbon monoxide in a solvent such as tetrahydrofuran oracetonitrile.

Procedure C

A compound of formula (VI) may be prepared as a reactive intermediate bycombining an aldehyde of formula (VIII) with a piperazine of formula(IV) ##STR16## wherein R³ to R⁶ and R⁸ and R⁹ are as defined herein, inthe presence of titanium tetrachloride or benzotriazole in a suitablesolvent such as toluene or dichloromethane, or for an intermediate offormula (VI) where W is benzotriazolyl, the reactive intermediate may beisolated, if desired, by crystallization or other appropriate means.

A compound of formula (I) may be obtained as a single enantiomericspecies by classical resolution with an enantiopure acid, such asmandelic acid, or by formation of readily separable diastereomers by anenantiopure derivatizing agent, or by chiral chromatography, or byenzymatic resolution of a compound of formula (I) or a suitablederivative, or by preparation of the compound of formula (I) fromenantiopure precursors, which may themselves be obtained as singleenantiomers by similar means.

Compounds of formula (III) may be obtained from the appropriate alcoholsof formula (IX), where the phenol is protected with a suitableprotecting group P, by methods such as halogenation with thionylchloride or triphenylphosphine/carbon tetrabromide, or reaction withmethanesulfonyl chloride or toluenesulfonyl chloride, in a solvent suchas dichloromethane. ##STR17##

Piperazines of formula (IV) are commercially available, or may beprepared by published procedures or variations of published procedureswhere R⁶ is varied by appropriate alkylation with agents R⁶ -X¹.

Compounds of formula (V) may be prepared by alkylation of a piperazineof formula (IV) with an alkylating agent of formula (X), in similarfashion to the piperazine alkylation described above. Alkylating agentsof formula (X) are likewise obtained from alcohols of formula (XI) bysimilar methods to those described above for compounds of formula (III).##STR18##

Alcohols of formula (IX) or (XI) may be prepared by low-temperature(e.g. -60° C. to -78° C.) addition of substituted arylmetallic species,prepared from compounds of formula (XII), wherein Z is reactive halogen(e.g. iodine or bromine), by methods described hereinabove, to protectedbenzaldehydes of formula (XIII). ##STR19##

Conversely, compounds of formula (IX) or (XI) may also be formed bysimilar addition of aforementioned protected phenylmetallic species(VII) to benzaldehydes of formula (VIII). ##STR20##

Compounds (VII), (VIII), (XII) and (XIII) and their suitably protectedderivatives may be prepared from commercially available materials bystandard literature procedures.

A compound of formula (I) may be convened into a pharmaceuticallyacceptable ester by reaction with an appropriate esterifying agent, e.g.an acid halide or anhydride. The compound of formula (I), includingesters thereof, may be converted into pharmaceutically acceptable saltsthereof in conventional manner, for example, by treatment with anappropriate acid. An ester or salt of a compound of formula (I) may beconverted into the parent compound, for example, by hydrolysis. Phenolicethers of a compound of formula (I) wherein P is C₁ -C₆ alkyl, may beprepared as described hereinbefore.

Based on the foregoing as well as general synthesis considerations, itwill be appreciated that various syntheses are useful for preparation ofdiarylmethyl piperazine compounds of the present invention, as will bereadily apparent to those of ordinary skill in the art. Illustrativesynthetic methods for production of compounds within the broad scope ofthe present invention are set out below by way of example, it beingunderstood that compounds of the invention are amenable to manufactureby various other synthesis routes and methods within the skill of theart, and that the illustrative synthesis methods set out below aretherefore not to be limitingly construed as regards the scope of theinvention. It is to be further appreciated that the novel compounds ofthe present invention comprehend various novel intermediates,precursors, pro-drugs, analogues, and derivatives of compoundsspecifically identified herein with reference to the invention.

When the synthesis procedures which are employed for producing compoundsof the invention yield racemic mixtures as reaction products, suchracemic mixtures may be resolved by suitable means and methodswell-known and established in the art, as for example by formation ofdiastereomeric salts with enantiopure carboxylic acids, by chiralchromatographic resolution, by enzymatic resolution, or by othersuitable conventional methods.

Synthesis Reaction Schemes

Set out below are illustrative synthetic schemes for the formation ofracemic(±)-3-((αR*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide,hereafter referred to as Compound (±)-C, which may be obtained as itsconstituent enantiomers by applying classical resolution or chiralsynthesis methods to the final product or to appropriate intermediates.Such methods are further illustrated for the obtention of preferredenantiomer(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide,referred to herein as Compound C, which is more specifically describedin Example 1 hereof. The illustrative synthesis schemes and resolutionmethodology of the ensuing description may likewise be employed in thesynthesis and resolution of other compounds of the invention, oralternatively other synthesis and/or resolution methodologies may beusefully employed within the skill of the art. ##STR21##

With respect to the foregoing synthesis scheme, the initial benzhydrylalcohol could be prepared from 3-(t-butyldimethylsilyloxy)bromobenzeneby the following scheme: ##STR22##

The intermediate could also be prepared via the benzophenone, which inturn could be obtained from an organometallic addition to4-bromobenzonitrile: ##STR23##

Other alternatives to intermediates involve condensation of anappropriately substituted piperazine with a carbonyl compound.Condensation with a benzaldehyde could provide an imminium salt thatcould add an aryllithium to provide benzhydryl piperazine compoundswherein X=CONEt₂, Y=CH₂ CH═CH₂, or wherein X=Br, Y=CH₂ CH═CH₂, asmixtures with their diastereomers, or protected precursors to thosecompounds. ##STR24##

Similarly, a "masked imminium" compound, where W is a suitable leavinggroup (e.g. benzotriazolyl or trichlorotitaniumoxy), may be treated withan arylmetal species (e.g. an aryllithium or an arylmagnesium bromidereagent), ##STR25## wherein the benzylpiperazine may dissociate togenerate the requisite imminium ion in situ. ##STR26##

Similarly, reductive amination of the appropriate benzophenone with asuitable piperazine may provide the desired compounds directly.##STR27##

Compound (±)-C can also be synthesized by the alternative syntheticroute set out below. ##STR28##

The trans-1-allyl-2,5-dimethylpiperazine reactant utilized in the abovesynthesis scheme may suitably be formed by the following syntheticprocess. ##STR29##

The racemic trans-1-allyl-2,5-dimethylpiperazine may be resolved intoits constituent enantiomers by classical resolution with an enantiopurecarboxylic acid to provide chiral intermediate(2R,5S)-1-allyl-2,5-dimethylpiperazine for the production of thepreferred (+)-antipode Compound C.

The (2R,5S)-1-allyl-2,5-dimethylpiperazine may also be made inenantiopure form, by the illustrative synthetic route outlined below.##STR30##

When the enantiopure (2R,5S)-1-allyl-2,5-dimethylpiperazine is treatedwith a racemic benzhydryl chloride, the resultant product is a mixtureof two enantiopure diastereomers that can be separated by conventionalmethods such as chromatography or fractional crystallization. ##STR31##

In addition to the foregoing, Compounds C or (±)-C may be synthesizedvia a nitrile synthesis route, utilizing cuprous cyanide as anitrilation agent, as shown below. ##STR32##

Alternative syntheses of Compound C from a corresponding halogenatedcompound are set out below. ##STR33##

The foregoing have been illustratively set out as examples of synthetictechniques which may be usefully employed to form compounds such asCompounds C or (±)-C, as well as other benzhydrylpiperazine compounds ofthe present invention, via corresponding or analogous reagents. Of theforegoing synthetic methods described to form Compound C, a synthesisroute employing (2R,5S)-1-allyl-2,5-dimethylpiperazine is empiricallypreferred due to its greater convenience as compared to the otherdescribed synthetic routes.

The features and advantages of the invention are more fully shown withrespect to the following non-limiting examples.

Certain specifications and methods common to many of the followingexamples relating to chemical synthesis are described in the nextparagraph.

Melting points were determined with a Thomas-Hoover apparatus and areuncorrected. All chemical reagents were purchased from Aldrich ChemicalCompany, Milwaukee, Wis., unless otherwise specified. Commercialsolvents were used without further purification except tetrahydrofuran,which was distilled from potassium metal. Nuclear magnetic resonance(NMR) spectra were variously obtained with Perkin-Elmer R-24, VarianXL-200, or XL-300 spectrometers. HPLC analyses were performed with aWaters liquid chromatography system equipped with a 700 Satellite WISP,600E System Controller and a 991 Photodiode Array detector, using eithera 4.6×250 mm Cyclobond I column (Advanced Separations Technologies,Whippany, N.J.) or a μ-Bondapak C-18 column (125 Å, 3.9×300 nm, WatersChromatography Division, Millipore Corporation, Milford, Mass.), at aflow rate of 1 ml/min. Analytical gas chromatography was performed on aHewlett-Packard Series II instrument, Model 5890 with flame ionizationdetector using helium as the carrier gas (injector temperature, 225° C.;detector temperature, 250° C.). Optical rotations were obtained with aPerkin-Elmer 241 polarimeter. Mass spectra were performed by OneidaResearch Services, Whiteshoro, N.Y. X-Ray crystallography was performedby Molecular Structure Corporation, College Station, Tex. Analyticalthin layer chromatography was performed on Analtech glass platespre-coated with silica gel GF (250 microns), and preparative thin layerchromatography on Analtech Uniplates pre-coated with silica gel GF (1000and 2000 microns). Elemental analyses were performed by AtlanticMicrolab, Norcross, Ga.

(REFERENCE) EXAMPLE 1(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

3-Iodobenzoic acid (55.5 g, 0.224 mol) was dissolved in tetrahydrofuran(220 mL) and oxalyl chloride (22 mL, 0.252 mol). Catalyticdimethylformamide (4 drops) was added, the solution was stirred at roomtemperature for 1 hour, and the solvent was removed under vacuum. Theresidue was dissolved in 220 mL petroleum ether (35°-60° C. boilingrange) and cooled to 0° C. in an ice bath. Diethylamine (55 mL, 0.532mol) was then added dropwise over 15 minutes. The reaction mixture wasstirred an additional 15 minutes in the ice bath, then diluted withethyl acetate (100 mL) and washed with saturated sodium chloridesolution (50 mL). The organic layer was separated, dried over magnesiumsulfate, and concentrated in vacuo to approximately half of the originalvolume. The solution was then filtered through a small pad of silicagel, using ethyl acetate to wash the pad. All volatiles were removed invacuo, and the product was dried under high vacuum to give 65.69 g (97%)of N,N-diethyl-3-iodobenzamide as an amber oil. NMR (300 MHz, CDCl₃): δ1.11 (br s, 3H); 1.21 (br s, 3H); 3.23 (br s, 2H); 3.51 (br s, 2H); 7.13(ddd, J₁ =0.8 Hz, J₂ =7.6 Hz, J₃ =7.6 Hz, 1H); 7.32 (ddd, J₁ =1.3 Hz, J₂=1.3 Hz, J₃ =7.5 Hz, 1H); 7.71 (d, J=1.2 Hz, 1H); 7.72 (ddd, J₁ =1.3 Hz,J₂ =1.3 Hz, J₃ =approx. 8.0 Hz (partially obstructed), 1H). Massspectrum (CI--CH₄) m/e: 304 (M+1, 100%). Calc. for C₁₁ H₁₄ NOI: C,43.58; H, 4.65; N, 4.62; I, 41.86. Found: C, 43.68; H, 4.64; N, 4.64; I,41.92.

3-Hydroxybenzaldehyde (70 g, 0.57 mol), tert-butyldimethylsilyl chloride(92 g, 0.61 mol), and imidazole (92 g, 1.35 mol) were combined indimethylformamide (250 mL). The mixture was stirred at room temperature,under nitrogen, for 1 hour. The solution was poured into water (1.5 L)and extracted with 2×500 mL petroleum ether (35°-60° C. boiling range).The organic solution was washed with saturated sodium chloride solution(100 mL), dried over magnesium sulfate, treated with silica gel (20 g),filtered, and concentrated in vacuo. The residue was dried further underhigh vacuum to yield 126.6 g (94%) of the air and light-sensitive3-((tert-butyldimethylsilyl)oxy)benzaldehyde as an amber oil. NMR (300MHz, CDCl₃): δ 0.22 (s, 6H); 0.99 (s, 9H); 7.10 (ddd, J₁ =1.2 Hz, J₂=2.5 Hz, J₃ =7.9 Hz, 1H); 7.32 (dd, J₁ =1.5 Hz, J₂ =2.4 Hz, 1H); 7.39(t, J=7.8 Hz, 1H); 7.47 (ddd, J₁ =1.3 Hz, J₂ 1.3 Hz, J₃ =7.6 Hz, 1H);9.95 (s, 1H). Mass spectrum (CI--CH₄) m/e: 237 (M+1, 100%). Calculatedfor C₁₃ H₂₀ O₂ Si: C, 66.05; H, 8.53. Found: C, 65.95; H, 8.56.

n-Butyllithium in hexanes (280 mL of a 2.5M solution) was added via adropping funnel to tetrahydrofuran (1.4 L) at -78° C., under nitrogen.When the n-butyllithium solution had cooled back to -78° C., a solutionof N,N-diethyl-3-iodobenzamide (106 g, 0.35 mol) in tetrahydrofuran (350mL) was added slowly over 20 minutes. The internal temperature rose to-65° C. during the addition. After the addition was complete, thesolution was stirred for 10 minutes, and a solution of3-((tert-butyldimethylsilyl)oxy)benzaldehyde (88 g, 0.37 mol) intetrahydrofuran (90 mL) was added slowly over 7 minutes. The reactionmixture was stirred for an additional 5 minutes at -78° C. and allowedto warm to -10° C. The mixture was poured into 875 mL petroleum ether(35°-60° C. boiling range) and sodium phosphate dibasic solution (350 mLof 2M aqueous solution), shaken, and the organic phase separated. Theorganic phase was dried over magnesium sulfate and concentrated invacuo. The residue was dissolved in an ethyl acetate-petroleum ethermixture (1:3, 90 mL), placed on a column of silica gel (1 kg), andwashed with ethyl acetate-petroleum ether (1:3) to remove fast elutingimpurities. Elution with ethyl acetate yielded, after in vacuoconcentration, 115.9 g (80%) of3-(3-((tert-butyldimethylsilyl)oxy)-α-hydroxybenzyl)-N,N-diethylbenzamideas a viscous amber oil. NMR (300 MHz, DMSO-d₆): δ 0.13 (s, 6H); 0.92 (s,9H); 0.98 (br s, 3H); 1.11 (br s, 3H); 3.10 (br s, 2H); 3.39 (br s, 2H);5.69 (d, J=4.1 Hz, 1H); 5.96 (d, J=4.2 Hz, 1H); 6.68 (dd, J₁ =1.9 Hz, J₂=7.7 Hz, 1H); 6.84 (s, 1H); 6.97 (d, J=7.7 Hz, 1H); 7.16 (d, J=approx. 8Hz (partially obscured), 1H); 7.17 (t, J=7.7 Hz, 1H); 7.28 (s, 1H); 7.35(t, J=7.8 Hz, 1H); 7.42 (d, J=7.6 Hz, 1H). Mass spectrum (CI--CH₄) m/e:414 (M+1, 11%), 178 (32%). Calc. for C₂₄ H₃₅ NO₃ Si: C, 69.69; H, 8.53;N, 3.39. Found: C, 69.65; H, 8.56; N, 3.40.

A 12 L, 3-necked round bottom flask was charged withtrans-2,5-dimethylpiperazine (767 g, 6.72 mol), which had beenrecrystallized from toluene to mp=115-119° C., and 600 mL of water. Theflask was cooled in an ice bath and a solution of methanesulfonic acid(1290 g, 13.4 mol) in 600 mL of water was added slowly with stirring andcooling to maintain the temperature below 40° C. The solution was cooledto 20° C. and 800 mL of ethanol was added. A 500 mL addition funnel wasfilled with 60% aqueous potassium acetate from a 2 L reservoir of thesolution, and potassium acetate was added to the reaction flask toadjust the pH to 4.0. A second addition funnel was charged with asolution of ethyl chloroformate (642 mL, 6.71 mol) in 360 mL oftetrahydrofuran. The ethyl chloroformate and potassium acetate solutionswere simultaneously added dropwise with adjustment of rate to maintainthe reaction solution at pH 4.0±0.1, with cooling as necessary tomaintain temperature at 25° C. After addition of the ethyl chloroformatewas complete, the reaction was stirred for 1 hour with continuedaddition of potassium acetate solution to maintain a pH of 4.0. Theorganic solvents were removed by distillation under vacuum. Theremaining aqueous solution was washed with 1500 mL of ethyl acetate toremove any bis-carbamate impurity. The ethyl acetate wash was extractedwith two 500 mL portions of 1M hydrochloric acid to recover desiredproduct. The acid extracts were combined with the original aqueoussolution and the pH was adjusted to 11 by addition of 10M sodiumhydroxide, with cooling to maintain temperature below 40° C. The aqueoussolution was extracted with two 1500 mL portions of ethyl acetate, thecombined extracts were dried over magnesium sulfate, and the solvent wasremoved to give 927 g (74%) ethyltrans-2,5-dimethyl-1-piperazinecarboxylate as a yellow oil.

A mixture of ethyl trans-2,5-dimethyl-1-piperazinecarboxylate (643 g,3.45 mol), allyl bromide (328 mL, 3.80 mol), and sodium carbonate (440g, 4.15 mol) in 2500 mL of acetonitrile was heated at reflux for 1.5hours. The reaction was cooled to room temperature, filtered, and thesolvent removed under vacuum. The residue was dissolved in 4000 mL ofdichloromethane and washed with two 500 mL portions of 1M sodiumhydroxide. The dichloromethane solution was dried over magnesium sulfateand the solvent was removed to give 630 g (81%) of ethyltrans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate as an oil.

Ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate (630 g, 2.78mol) was added to a solution of 87% potassium hydroxide pellets (2970 g,46 mol) in 4300 mL of 95% ethanol and heated at reflux for 1.5 hours.Carbon dioxide evolution was observed for the first 0.5-1 hour ofheating. The reaction was cooled below reflux temperature and 2000 mL oftoluene was carefully added. Ethanol was removed by azeotropicdistillation at 105° C., while adding an additional 4000 mL of tolueneto the reaction flask during the course of the distillation. Aftercollection of 9000 mL of distillate, the reaction was cooled to 100° C.and 1000 mL of toluene was carefully added. The solution was slowlycooled to 5° C. and maintained at 5° C. for 30 minutes. The solution wasfiltered, and the filter cake was washed with an additional 1500 mL oftoluene. The filtrate was washed with 1000 mL of water, dried overmagnesium sulfate, and the solvent was removed to give 296 g (69%) oftrans-1-allyl-2,5-dimethylpiperazine as a dark liquid. NMR (300 MHz,DMSO-d₆): δ 0.87 (d, J=6.3 Hz, 3H); 0.92 (d, J=6.3 Hz, 3H); 1.63 (t,J=11 Hz, 1H); 2.05 (m, 1H); 2.30 (t, J=11 Hz, 1H); 2.6-2.8 (m, 4H); 3.33(dd, J₁ =5 Hz, J₂ =14 Hz, 1H); 5.09 (d, J=8.7 Hz, 1H); 5.13 (d, J=14 Hz,1H) 5.8 (m, 1H).

Di-p-toluoyl-D-tartaric acid (Schweizerhall, Inc., South Plainfield,N.J.) (1.25 Kg, 3.2 mol) was dissolved in hot (˜60° C.) 95% ethanol (16L) and racemic trans-1-allyl-2,5-dimethylpiperazine (500 g, 3.2 mol) wasadded in several portions (caution: exothermic). The hot solution wasseeded with crystals of the diastereoisomerically pure salt (obtainedfrom a previous small-scale resolution) and cooled to room temperatureover 2-3 hours. The solution was slowly stirred for 2 days at roomtemperature. The resulting salt was collected by filtration, washedtwice with 95% ethanol, and dried under vacuum to give 826.5 g of awhite solid (47%). The process was repeated with a second batch of thedi-p-toluoyl-D-tartaric acid and racemictrans-1-allyl-2,5-dimethylpiperazine to give 869 g (50%).

The total of 1695 g of salt was divided into three batches and eachbatch was recrystallized twice in the following fashion. The salt wasdissolved in refluxing 95% ethanol (˜2.7 L/100 g of salt), andapproximately half of the ethanol was removed by distillation. (Note:vigorous stirring was necessary during distillation to preventcrystallization on the vessel wail.) The hot solution was seeded withcrystals of the pure diastereomeric salt, cooled to room temperature,and stirred slowly for 2 days before collecting the salt by filtration.(Note: a subsequent experiment suggested that crystallization time canbe reduced from 2 days to 8 hours.) The total amount recovered was 1151g. The salt was dissolved in 3 L of 2M aqueous sodium hydroxide, and theaqueous solution was extracted with four 1 L portions ofdichloromethane. The organic extracts were combined, dried over sodiumsulfate, and solvent removed by rotary evaporation (temperature <20° C.)to give 293 g (29% based on racemic weight) of2R,5S-1-allyl-2,5-dimethylpiperazine as a clear oil. α!_(D) ²⁰ =-55°(abs. ethanol, c=1.2). The trifluoroacetamide of the product wasprepared with trifluoroacetic anhydride and analyzed by chiral capillarygas chromatography (Chiraldex B-PH column, 20 m×0.32 mm, AdvancedSeparation Technologies Inc., Whippany, N.J., 120° C.) indicating anenantiopurity of >99% ee (retention time of desired enantiomer, 11.7min; other enantiomer, 10.7 min).

3-(3-((tert-Butyldimethylsilyl)oxy)-α-hydroxybenzyl)-N,N-diethylbenzamide(115.9 g, 0.280 mol) was dissolved in tetrahydrofuran (560 mL) andthionyl chloride (24.5 mL, 0.336 mol) was added. The reaction wasnoticeably exothermic. The mixture was stirred for 15 minutes andconcentrated in vacuo (cautiously at first, due to rapid gas evolution).After all volatiles were removed, the crude3-(3-((tert-butyldimethylsilyl)oxy)-α-chlorobenzyl)-N,N-diethylbenzamidewas dissolved in acetonitrile (560 mL). Sodium iodide (42 g, 0.280 mol),diisopropylethylamine (73 mL, 0.42 mol), and(2R,5S)-1-allyl-2,5-dimethylpiperazine (52.5 g, 0.280 mol) were added.The mixture was stirred at reflux, under nitrogen, for 2.5 hours. Theacetonitrile was removed by distillation, under nitrogen, over the nexthour. After cooling, the reaction mixture was poured into ethyl acetate(1.1 L) and potassium carbonate solution (350 mL of a 2M aqueoussolution), and shaken. The organic phase was separated, dried over solidpotassium carbonate, and concentrated in vacuo. The residue wasdissolved in ethyl acetate-petroleum ether (1:1, 150 mL), and placed ona column of silica gel (3 kg). Elution with ethyl acetate-petroleumether (1:1) afforded the desired isomer as the first of the two epimersto elute. The eluate solution was concentrated to a small volume andallowed to stand for 12 hours. A crystalline impurity that precipitatedwas removed by filtration, and the filtrate was concentrated to dryness.

The residue was dissolved in tetrahydrofuran-petroleum ether (1:1, 125mL) and extracted with 350 mL of 0.75M hydrochloric acid. The aqueousphase, containing the desired product, was stirred at room temperaturefor 24 hours to cleave the silyl ether. The solution was then washedwith 1:1 ethyl acetate-petroleum ether (2×100 mL). The aqueous solutionwas stirred with ethyl acetate (100 mL) while solid sodium bicarbonate(38 g) was added portionwise, with caution (vigorous gas evolution).After 15 minutes of additional stirring, the layers were separated andthe aqueous layer extracted again with ethyl acetate (100 mL). The twoethyl acetate portions were combined, dried over sodium sulfate,concentrated in vacuo, and dried under high vacuum to yield 37.3 g (30%)of(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamideas an off-white solid. α!_(D) ²⁰ +20° (methanol, c=2). NMR (400 MHz,DMSO-d₆): δ 0.91 (d, J=6.2 Hz, 3H); 0.99 (br s, 3H); 1.05 (d, J=6.2 Hz,3H); 1.09 (br s, 3H); 1.84 (dd, J₁ =7.3 Hz, J₂ =10.9 Hz, 1H); 2.06 (dd,J₁ =7.3 Hz, J₂ =10.9 Hz, 1H); 2.48 (m, 1H); 2.51 (dd, J₁ =2.7 Hz, J₂=10.9 Hz, 1H); 2.58 (br s, 1H); 2.70 (dd, J₁ =2.7 Hz, J₂ =10.9 Hz, 1H);2.81 (dd, J₁ =7.0 Hz, J₂ =13.9 Hz, 1H); 3.12 (br s, 2H); 3.15 (dd, J₁=5.1 Hz, J₂ =13.9 Hz, 1H); 3.38 (br s, 2H); 4.97 (br s, 1H); 5.07 (d,J=10.2 Hz, 1H), 5.14 (d, J=16.9 Hz, 1H); 5.70-5.82 (m, 1H); 6.64 (dd, J₁=2.1Hz, J₂ =8.0 Hz, 1H); 6.65 (s, 1H); 6.68 (d, J=7.7 Hz, 1H); 7.11 (t,J=8.0 Hz, 1H); 7.14 (d, J=7.6 Hz, 1H); 7.30 (s, 1H); 7.33 (t, J=7.6 Hz,1H); 739 (d, J=8.0 Hz, 1H); 9.31 (s, 1H). Mass spectrum (CI--CH₄) m/e:436 (M+1, 53%). Calc. for C₂₇ H₃₇ N₃ O₂ 0.5 H₂ O: C, 72.94; H, 8.61; N,9.45. Found: C, 73.00; H, 8.57; N, 9.40. The free amine (32.2 g) wasdissolved in 200 mL of absolute ethanol and titrated with ethanolichydrogen chloride (7M and 1M) to a pH of 3.95. The solvent was removedand the residue was redissolved in 50 mL of dichloromethane. Diethylether (900 mL) was added with vigorous stirring to precipitate a gummyproduct which solidified upon stirring overnight under nitrogen. Theproduct was collected by filtration and dried under vacuum at 55° C. togive 33.06 g (91% recovery) of the monohydrochloride salt. Calc. for C₂₇H₃₇ N₃ O₂ HCl H₂ O: C, 66.17; H,8.23; N, 8.57; Cl, 7.23. Found: C,66.40; H,8.17; N, 8.48; Cl, 7.28.

EXAMPLE 2(+)-3-((αR)-α-((2S,5R)-2.5-Dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

A mixture of(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamidemonohydrochloride (8.22 g, 17.1 mmol, Example 1) and 5.45 g (2.5 mmol)of 5% palladium on charcoal in 160 ml of methanol:water/3:1 was heatedat reflux for 20 hours. The reaction mixture was filtered through Celiteunder nitrogen and the filtrate was evaporated. The residue was dilutedwith water and the pH was adjusted to 8 with aqueous 1M sodiumhydroxide. The mixture was extracted with ethyl acetate, dried oversodium sulfate, and evaporated to give 5.05 g (75%) of(+)-3-((αR)-α-((2S,5R)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamideas a light yellow solid. NMR (DMSO-d₆, 200 MHz): δ 1.1 (m, 12H); 2.0 (m,1H); 2.6-2.9 (m, 3H); 3.0-3.5 (m, 7H); 5.25 (s, 1H); 6.7 (m, 3H); 7.2(m, 3H); 7.4 (m, 2H); 9.5 (s, 1H). α!_(D) ²⁰ =+11.9° (abs ethanol,c=2.3). Titration of 0.20 g of product with ethanolic hydrogen chloridein ethanol solution to pH 3.5 and precipitation from dichloromethanewith diethyl ether gave 0.103 g (47% recovery) of the monohydrochloridesalt as an off-white solid. Calc. for C₂₄ H₃₃ N₃ O₂ HCl 0.75 H₂ O: C,64.70; H, 8.03; N, 9.43; Cl, 7.96. Found: C, 64.97; H, 7.97; N, 9.38;Cl, 8.04. Mass spectrum (CI--CH₄) m/e 396 (M+1, 38%); 282 (39%); 115(100%).

EXAMPLE 3(+)-3-((αR)-α-((2S,5R)-2,5-Dimethyl-4-ethyl-1-piperazinyl)-3-hydroxy-benzyl)-N,N-diethylbenzamide

A solution of(+)-3-((αR)-α-((2S,5R)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide(0.30 g, 0.76 mmol, Example 2) in 1.5 mL of 2M ethanolic hydrogenchloride was evaporated to dryness. The residue was dissolved in 7 mL ofacetone:water (3:2). Sodium acetate trihydrate (0.28 g, 2.02 mmol),acetaldehyde (40 mL, 0.71 mmol) and sodium cyanoborohydride (0.072 g,1.1 mmol) were added. After stirring at room temperature under nitrogenfor 18 hours, the mixture was acidified with aqueous 6M hydrochloricacid to pH 2 and extracted with diethyl ether. The aqueous layer wasadjusted to pH 8 with 10M aqueous sodium hydroxide. The resultingsuspension was extracted with ethyl acetate, and the extracts were driedover sodium sulfate and evaporated to dryness to give 0.21 g of a yellowoil. Purification by thin layer chromatography on silica gel plates withdichloromethane:ethanol:ammonium hydroxide/90:10:1 gave 0.12 g (38%) of(+)-3-((αR)-α-((2S,5R)-2,5-dimethy-4-ethyl-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamideas a light beige solid. NMR (DMSO-d₆, 300 MHz): δ 0.9 (d, J=6 Hz, 3H);1.1 (d, J=6 Hz, 3H); 1.0 (br m, 6H); 1.8 (m, 1H); 2.05 (dd, J₁ =11 Hz,J₂ =8 Hz, 1H); 2.25 (dd, J₁ 13 Hz, J₂ =6 Hz, 1H); 2.6 (m, 4H); 2.7 (d,J=11 Hz, 1H); 3.1 (br m, 2H); 3.4 (br m, 2H); 5.0 (s, 1H); 6.65 (m, 3H);7.1(d, J=8 Hz, 1H); 7.15 (d, J=8 Hz, 1H); 7.35 (m, 3H); 9.3 (s, 1H).α!_(D) ²⁰ =+2.1° (abs ethanol, c=0.96). The product was dissolved inabsolute ethanol and titrated to pH 3 with ethanolic hydrogen chloride,concentrated and treated with diethyl ether to precipitate 0.111 g (85%recovery) of the monohydrochloride salt as a white powder. Calc. for C₂₆H₃₇ N₃₀ ₂ HCl H₂ O: C, 65.32; H, 8.43; N, 8.79; Cl, 7.42. Found: C,65.23; H, 8.15; N, 8.82: Cl, 7.53.: Mass spectrum (CI--CH₄) m/e 424(M+1, 100%); 423 (M, 20%); 282 (12%); 141 (14%).

EXAMPLE 4(+)-3-((αR*)-α-((2S*,5R*)-2,5-Dimethyl-4-propyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

(+)-3-((αR*)-α-((2S*,5R*)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide,the racemate of Example 1, was prepared according to the procedure ofExample 1 using racemic trans-N-allyl-2,5-dimethylpiperazine. Thematerial was de-allylated by the procedure of Example 2 to give(+)-3-((αR*)-α-((2S*,5R*)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide(1.8 g, 4.6 mmol), which was treated with tert-butylchlorodimethylsilane(1.38 g, 9.2 mmol) and imidazole (0.78 g, 11.4 mmol) indimethylformamide at room temperature under nitrogen overnight. Thereaction mixture was poured into ice-water and extracted with diethylether. The ethereal layers were washed with water and brine, dried oversodium sulfate and the solvent was evaporated to give 1.61 g (69%) ofthe tert-butyldimethylsilyl ether as a beige solid. The product (0.30 g,0.59 mmol) was alkylated with 1-iodopropane (63 mL, 0.65 mmol) andanhydrous sodium carbonate (0.31 g, 2.95 mmol) in tetrahydrofuran atreflux for 3 days. The solvent was evaporated and the residue was takenup in dichloromethane and filtered to remove the insoluble salts. Thefiltrate was evaporated to give 0.30 g of a dark yellow oil. The crudeproduct was deprotected with tetraethylammonium fluoride dihydrate (0.15g, 0.81 mmol) in acetonitrile at room temperature. The solvent wasevaporated and the residue was taken up in aqueous 1M hydrochloric acidand extracted with diethyl ether. The aqueous layer was adjusted to pH 8with aqueous sodium hydroxide and extracted with ethyl acetate. Theethyl acetate extracts were dried over sodium sulfate and evaporated togive 0.15 g (63%) of(±)-((αR*)-α-((2S*,5R*)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamideas a beige solid. NMR (DMSO-d₆, 200 MHz): δ 0.8 (t, J=8 Hz, 3H); 0.9 (d,J=6 Hz, 3H); 1.05 (d, J=6 Hz, 3H); 1.0 (br m, 6H); 1.3 (m, 2H); 1.9 (m,1H); 2.1 (m, 2H); 2.4-2.7 (m, 4H); 2.8 (d, J=10 Hz, 1H); 3.1 (br m, 2H);3.4 (m, 2H); 5.0 (s, 1H); 6.7 (m, 3H); 7.1 (m, 2H); 7.4 (m, 3H); 9.35(s,1H). The product was dissolved in ethanol and titrated to pH 3 withethanolic hydrogen chloride to give 0.073 g (45%) of themonohydrochloride as a white powder. Calc. for C₂₇ H₃₉ N₃ O₂ HCl 0.75 H₂O: C, 66.51; H, 8.58; N, 8.62; Cl, 7.27. Found: C, 66.32; H, 8.49; N,8.58; Cl, 7.32. Mass spectrum (CI--CH₄) m/e: 438 (M+1, 76%).

EXAMPLE 5

(-)-3-((αR)-α-((2S,5R)-2,5-Dimethyl-4-(2-propynyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamidewas prepared by alkylation of the compound of Example 2 with propargylbromide and deprotected by methods similar to that in Example 4. NMR(DMSO-d₆, 200 MHz): δ 0.9 (d, J=6 Hz, 3H); 1.05 (d, J=6 Hz, 3H); 1.1 (brm, 6H); 1.75 (m, 2.3-2.7 (m, 5H); 3.1-3.5 (m, 7H); 5.25 (s, 1H); 6.7 (m,3H); 7.1-7.5 (m, 5H); 9.4 (s,1H). α!_(D) ²⁰ =-12.9° (absolute ethanol,c=1.0). Calc. for C₂₇ H₃₅ N₃ O₂ HCl 0.75 H₂ O: C, 67.06; H, 7.82; N,8.69; Cl, 7.33. Found: C, 66.87; H, 7.78; N, 8.65; Cl, 7.35. Massspectrum (CI--CH₄) m/e: 434 (M+1, 100%); 433 (M, 13%); 282 (28%); 151(42%).

EXAMPLE 6

(±)-3-((αR*)-α-((2S*,5R*)-2,5-Dimethyl-4-phenethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamidewas prepared according to the procedure of Example 4 with phenethylbromide. NMR (DMSO-d₆, 200 MHz): δ 0.8-1.2 (m, 12H); 1.9 (m, 1H);2.0-3.0 (m, 9H); 3.1 (br m, 2H); 3.3 (br m, 2H) 5.0 (s, 1H); 6.7 (m,3H); 7.1-7.5 (m, 10H); 9.4 (s,1H). Calc. for C₃₂ H₄₁ N₃ O₂ HCl 0.75 H₂O: C, 69.92; H, 7.98; N, 7.64; Cl, 6.45. Found: C, 69.65; H, 7.94; N,7.62; Cl, 6.45. Mass spectrum (CI--CH₄) m/e: 500 (M+1, 25%); 282 (14%);284 (100%); 217 (84%).

EXAMPLE 7(+)-3-((αR)-α-((2S,5R)-2,4,5-Trimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

(+)-3-((αR)-α-((2S,5R)-2,5-Dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide(Example 2, 1.00 g, 2.53 mmol) was combined with 0.4 mL (10.1 mmol) of96% formic acid and 0.56 mL (7.6 mmol) of 37% aqueous formaldehyde. Themixture was kept at 80° C. for 18 hours, cooled to room temperature,treated with 6 mL of aqueous 6M hydrochloric acid and extracted withdiethyl ether. The aqueous layer was diluted with water and adjusted topH 8 with aqueous 10M sodium hydroxide. The resulting slurry wasextracted with dichloromethane. The combined organic layers were driedover sodium sulfate and evaporated to give 1.12 g of a beige solid.Chromatography on silica gel with dichloromethane:ethanol (1 to 7%) gave0.62 g (60%) of(+)-3-((αR)-α-((2S,5R)-2,4,5-trimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-di-ethylbenzamideas an off-white solid. NMR (DMSO-d₆, 200 MHz): δ 0.9 (d, J=6 Hz, 3H);1.05 (d, J=6 Hz, 3H); 1.0 (br m, 6H); 1.75 (t, J=9 Hz, 1H); 2.0 (t, J=10Hz, 1H); 2.1 (s, 3H); 2.1 (m, 1H); 2.5 (m, 2H); 2.7 (d, J=9 Hz, 1H); 3.2(br m, 2H); 3.4 (br m, 2H) 5.2 (s, 1H); 6.7 (m, 3H); 7.2 (m, 2H); 7.3(s, 1H); 7.4 (m, 2H); 9.4 (s, 1H). α!_(D) ²⁰ =+17.7° (absolute ethanol,c=2.2). The product was titrated to pH 3 with ethanolic hydrogenchloride to give 0.503 g (74% recovery) of the monohydrochloride salt asa whim powder. Calc. for C₂₅ H₃₅ N₃ O₂ HCl 0.75 H₂ O: C, 65.34; H, 8.22;N, 9.14; Cl, 7.71. Found: C, 65.07; H, 8.16; N, 9.07; Cl, 7.70. Massspectrum (CI--CH₄) m/e: 410 (M+1, 100%).

EXAMPLE 8

(-)-3-((αR)-α-((2S,5)-4-(Cyclopropylmethyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamidewas prepared by alkylation of the compound of Example 2 with(bromomethyl)-cyclopropane by the method in Example 4. NMR (DMSO-d₆, 200MHz): δ 0.05 (m, 2H); 0.4 (d, J=8 Hz, 2H); 0.8 (m, 1H); 0.9 (d, J=6 Hz,3H); 1.1 (d, J=6 Hz, 3H); 1.1 (br m, 6H); 1.8 (dd, J₁ =11 Hz, J₂ =9 Hz,1H); 2.2 (m, 2H); 2.4 (dd, J₁ =13 Hz, J₂ =8Hz, 1H); 2.6 (m, 3H); 2.9 (d,J=9 Hz, 1H); 3.2 (br m, 2H); 3.4 (br m, 2H); 5.0 (s, 1H); 6.7 (m, 3H);7.1 (m, 2H); 7.4 (m, 3H); 9.4 (s, 1H). α!_(D) ²⁰ =-0.9° (absoluteethanol, c=2.9). Calc. for C₂₈ H₃₉ N₃ O₂ HCl 0.75 H₂ O: C, 67.31; H,8.37; N, 8.41; Cl, 7.10 Found: C, 67.34; H, 8.39; N, 8.42; Cl, 7.15.Mass spectrum (CI--CH₄) m/e 450 (M+1, 100%), 449 (M, 28%), 282 (20%),167 (35%).

EXAMPLE 9(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-phenylbenzamide

A mixture of 1400 g (8.1 mol) of 3-bromophenol, 1218 g (8.1 mol) oftert-butylchlorodimethylsilane and 1376 g (20.2 mol) of imidazole in1600 mL of N,N-dimethylformamide was stirred at room temperature undernitrogen for 18 hours. The reaction mixture was poured into pH 8 aqueousbuffer solution and extracted with diethyl ether. The ether extractswere washed with water and brine, dried over sodium sulfate, and thesolvent was evaporated under vacuum to give 2314 g of crude3-bromophenyl tert-butyldimethylsilyl ether as an orange oil. NMR(CDCl₃, 200 MHz) δ: 0.2 (s, 6H); 0.95 (s, 9H); 6.8 (m, 1H); 7.0-7.1 (m,3H).

The silyl ether (1771 g, 6.17 mol) was dissolved in 4 L of drytetrahydrofuran, dried further over molecular sieves, then transferredto a 12 L reaction flask under nitrogen and cooled to -78° C.n-Butyllithium (2400 mL of a 1.6M solution in hexane) was added, whilestirring under nitrogen, at a rate to keep the temperature below -70° C.Stirring was continued at -78° C. for 2 hours. A solution of3-bromobenzaldehyde (1119 g, 6.05 mol) in 600 mL of dry tetrahydrofuranwas added at a rate to keep the reaction temperature below -70° C. Afterstirring for 2 hours at -78° C., the reaction was quenched with 1400 mLof saturated aqueous ammonium chloride and allowed to warm to roomtemperature. The mixture was filtered to remove solids and the layerswere separated. The organic phase was washed with brine, dried oversodium sulfate and evaporated to give 2500 g of crudeα-(3-bromophenyl)-3-(tert-butyldimethylsilyloxy)-benzyl alcohol as ayellow oil. Chromatography on silica gel of 1 kg of the crude productwith hexane:dichloromethane (gradient from 90:10 to 75:25, followed bydichloromethane:ethyl acetate/90:10) gave 692.3 g ofα-(3-bromophenyl)-3-(tert-butyldimethylsilyloxy)benzyl alcohol as ayellow oil. NMR (CDCl₃, 200 MHz) δ: 0.2 (s, 6H); 0.95 (s, 9H); 2.3 (brs, 1H); 5.7 (s, 1H); 6.75 (d, J=8 Hz, 1H); 6.8 (s, 1H); 6.9 (d, J=8 Hz,1H); 7.2 (m, 2H); 7.3 (d, J=8 Hz, 1H); 7.4 (d, J=8 Hz, 1H); 7.5 (s, 1H).

Thionyl chloride (38 mL, 0.51 mol) was added dropwise to a solution ofthe benzhydryl alcohol (160 g, 0.41 mol) in 1 L of dichloromethane andthe mixture was stirred overnight at room temperature. The solvent wasremoved under vacuum, the residue was redissolved in toluene, and thesolvent was again removed under vacuum to eliminate excess thionylchloride to give crudeα-(3-bromophenyl)-3-(tert-butyldimethylsilyloxy)benzyl chloride as abrown oil. NMR (CDCl₃, 200 MHz) δ: 0.2 (s, 6H); 0.95 (s, 9H); 6.0 (s,1H); 6.8-7.0 (m, 3H); 7.2-7.6 (m, 5H).

A mixture of the benzhydryl chloride and(-)-(2R,5S)-1-allyl-2,5-dimethylpiperazine (137.6 g, 0.89 mol, fromExample 1, infra) in 1500 mL of acetonitrile was heated at reflux for 48hours, concentrated in vacuo, and the residue dissolved in ethylacetate. The mixture was washed with 0.25M aqueous sodium hydroxide,dried over sodium sulfate and concentrated in vacuo to give 202.6 g ofdark oil, which was dissolved in acetonitrile (1 L) and treated withtetraethylammonium fluoride dihydrate (88.9 g, 0.48 mol). After stirringat room temperature overnight, the solvent was removed under vacuum. Theresidue was dissolved in dichloromethane (2 L), washed with pH 8 aqueousbuffer solution, dried over sodium sulfate and concentrated down to adark oil which was stirred in acetonitrile (700 mL) at 25° C. for 72hours to produce a tan precipitate. Recrystallization from acetonitrile(2 L) gave 35.3 g of a single diastereomer: (+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-bromobenzyl)phenol as a whitesolid. NMR (DMSO-d₆, 200 MHz) δ: 0.95 (d, J=6 Hz, 3H); 1.03 (d, J=6 Hz,3H); 1.8 (dd, J₁ =6 Hz, J₂ =10 Hz, 1H); 2.1 (dd, J₁ =6 Hz, J₂ =10 Hz,1H); 2.1 (dd, J₁ 6 Hz, J₂ =10 Hz, 1H); 2.4-2.6 (m, 3H); 2.7 (d, J=11 Hz,1H); 2.8 (dd, J₁ =7 Hz, J₂ =14 Hz, 1H); 3.2 (dd, J₁ =6 Hz, J₂ =13 Hz,1H); 4.9 (s, 1H); 5.1 (d, J=10 Hz, 1H); 5.2 (d, J=18 Hz, 1H); 5.7-5.9(m, 1H); 6.6-6.8 (m, 3H); 7.0-7.4 (m, 4H); 7.55 (s, 1H); 9.35 (s, 1H).The mother liquor was evaporated to give 127 g of a brown solid. Aportion (11 g) of this solid was purified by chromatography on silicagel with dichloromethane:ethanol (0-2.5%). The first isomer to elutefrom the column was collected to give 2.32 g of3-((αS)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-bromo-benzyl)phenolas a light yellow solid. NMR (DMSO-d₆, 200 MHz) δ: 0.95 (d, J=6 Hz, 3H);1.05 (d, J=6 Hz, 3H); 1.85 (dd, J₁ =7 Hz, J₁ =9 Hz, 1H); 2.1 (dd, J₁ =6Hz, J₂ =9 Hz, 1H); 2.5 (m, 3H); 2.7 (dd, J₁ =2 Hz, J₂ =8 Hz, 1H); 2.9(dd, J₁ =7 Hz, J₂ =7 Hz, 1H); 3.1 (dd, J₁ =5 Hz, J₂ =9 Hz, 1H); 4.95 (s,1H); 5.1 (d, J=10 Hz, 1H); 5.2 (d, J=17 Hz, 1H); 5.8 (m, 1H); 6.6 (d,J=8 Hz, 1H); 6.8 (m, 2H); 7.1 (t, J=8 Hz, 1H); 7.3 (m, 2H); 7.5 (m, 2H);9.3 (s, 1H).

(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-bromobenzyl)phenol(147.3 g, 0.355 mol) was dissolved in 1 L of N-methyl-2-pyrrolidinonewith cuprous cyanide (63.6 g, 0.71mol), and the reaction was heated at170° C. for 30 hours. The reaction was cooled to room temperature andpoured into 7 L of aqueous 14% sodium cyanide. The mixture was stirredovernight and extracted with ethyl acetate. The ethyl acetate extractswere combined, washed with water, dried over sodium sulfate andconcentrated in vacuo to give 133.3 g of a brown solid. Chromatographyon silica gel with ethanol (2-7%) in dichloromethane gave 97.8g of crude(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzonitrile.Recrystallization from acetonitrile gave 74.2 g (58%) pure(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzonitrileas a white solid.

The benzonitrile (78.8 g, 0.22 mol) was combined with 60 g of sodiumhydroxide pellets in 1 L of 95% ethanol and heated at reflux for 72hours. The mixture was concentrated in vacuo to remove ethanol. Theresidue was dissolved in water and the resulting solution was adjustedto pH 5 with concentrated hydrochloric acid. The solvent was removed invacuo to give 138.8 g of the3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoicacid as a mixture with sodium chloride. A portion (5.0 g) of the crudeacid was stirred with 50 mL of water. The resulting slurry was filtered,the solid in the filter was washed three times with water then driedunder vacuum for three hours to give 2.02 g of(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoicacid as a light beige solid. NMR (DMSO-d₆, 200 MHz) δ: 0.95 (d, J=6 Hz,3H); 1.1 (d, J=6 Hz, 3H); 1.9 (ddd, J₁ =3 Hz, J₂ =7 Hz, J₃ =10 Hz, 1H);2.1 (dd, J₁ =8 Hz, J₂ =10 Hz, 1H); 2.5 (m, 2H); 2.7-2.9 (m, 2H); 3.2 (m,2H); 5.05 (d, J=12 Hz, 1H); 5.2 (d, J=18 Hz, 1H); 5.8 (m, 1H); 6.7 (m,3H); 7.1 (t, J=8 Hz, 1H); 7.4 (t, J=8 Hz, 1H); 7.65 (d, J=8 Hz, 1H); 7.8(d, J=8 Hz, 1H); 8.0 (s, 1H); 9.4 (s, 1H). α!_(D) ²⁰ =+4.1° (0.1Maqueous sodium hydroxide, c=1.09). Calc. for C₂₃ H₂₈ N₂ O₃ 0.75 H₂ O: C,70.12; H, 7.55; N, 7.11. Found: C, 70.23; H, 7.35; N, 7.10. Massspectrum (CI--CH₄) m/e: 381 (M+1, 35%); 380 (M, 2%); 227 (28%); 155(100%); 153 (83%).

3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoicacid (25.9 g of a 50% by weight mixture with sodium chloride, 34.0 mmol)was dissolved in 40 mL of dimethylformamide with 12.8 g (84.9 mmol) oftert-butylchlorodimethylsilane and 11.5 g (169.1 mmol) of imidazole andstirred overnight at room temperature. The reaction solution was pouredinto 500 mL of ice water and extracted with 500 mL of diethyl ether. Theether extract was washed twice with 250 mL of water, and then with 125mL of saturated sodium chloride solution. The ether solution was driedover sodium sulfate and the solvent was removed to give 20.8 g of crudetert-butyldimethylsilyl3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)-benzoate.

The crude silyl ether-silyl ester (20.7 g,≦33.9 mmol based on theprevious reaction) was dissolved in 60 mL of dichloromethane and cooledto 0° C. under nitrogen. Oxalyl chloride (3.7 mL, 42.4 mmol) was addeddropwise. While maintaining the bath temperature at 0° C., catalyticdimethylformamide (10 drops) was added slowly. Evolution of gas wasevident during the addition of dimethylformamide. The bath temperaturewas maintained at 0° C. for 30 minutes, then allowed to warm to roomtemperature. The solution was stirred at room temperature, undernitrogen for 24 hours. All of the volatiles were removed by evaporationunder reduced pressure to give 29.76 g of crude3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoylchloride as a yellow-brown solid. The crude acid chloride was usedwithout purification.

Benzamide-Formation Method

3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoylchloride (2.33 g. crude, approx-imately 1.44 g. actual compound, 2.81mmol based on 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoic acid)was dissolved in 12 mL of dichloromethane at room temperature undernitrogen. Triethylamine (0.5 mL) was added to the solution.N-methylaniline (0.46 mL, 4.3 mmol) was added dropwise to the solution(exothermic), and the reaction was stirred overnight at roomtemperature. All volatiles were removed by evaporation under reducedpressure to provide a gummy brown solid.

This crude solid was dissolved in acetonitrile (8 mL) under nitrogen atroom temperature. Tetraethylammonium fluoride hydrate (1.19 g, 6.42mmol) was added and the solution was stirred for 1 hour at roomtemperature. After removal of solvent, the residue was purified bychromatography on silica gel (4 cm×12 cm) with 0.5-2% ethanol indichloromethane to give 0.368 g (28% over 4 steps from3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoicacid) of(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(hydroxybenzyl)-N-methyl-N-phenylbenzamideas a light yellow solid. NMR (300 MHz, DMSO-d₆): δ 0.89 (d, J=6.0 Hz,3H); 0.96 (d, J=6.0 Hz, 3H); 1.66 (dd, J₁ =7.3 Hz, J₂ =11.4 Hz, 1H);2.01 (dd, J₁ =7.8 Hz, J₂ =10.6 Hz, 1H); 2.26 (br d, J=10.6 Hz, 1H);2.37-2.54 (m, 2H); 2.66 (br d, J=11.0 Hz, 1H); 2.82 (dd, J₁ =7.0 Hz, J₂=13.9 Hz, 1H); 3.17 (dd, J₁ =4.8 Hz, J₂ =13.9 Hz, 1H); 3.34 (s, 3H);4.77 (s, 1H); 5.10 (d, J=10.1 Hz, 1H); 5.16 (d, J=17.3 Hz, 1H);5.70-5.82 (m, 1H); 6.41 (d, J=7.4 Hz, 1H); 6.54 (s, 1H); 6.64 (d, J=8.0Hz, 1H); 7.05-7.26 (m, 10H); 9.31 (s, 1H). Mass spectrum (CI--CH₄) m/e:470 (M+1, 100%), 376 (81%), 316 (45%), 153 (97%). α!_(D) ²⁰ =+12.3°(ethanol, c=1.2). The free amine (0.339 g) was dissolved in ethanol andtitrated with ethanolic hydrogen chloride to pH 3.0 followed byprecipitation with diethyl ether from dichloromethane to give 0.321 g(88% recovery) of the monohydrochloride salt as a hygroscopic lightyellow powder. Calc. for C₃₀ H₃₅ N₃ O₂ HCl H₂ O: C, 68.75; H, 7.31; N,8.02; Cl, 6.76. Found: C, 68.86; H, 7.42; N, 8.00; Cl, 6.84.

EXAMPLE 10(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-(dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-fluorophenyl)-N-methylbenzamide

Following a general literature procedure for reductive alkylation(Krishnamurthy, S. Tetrahedron Lett. 1982, 23, 3315) acetic-formicanhydride was prepared by slowly adding formic acid (7.5 mL) to aceticanhydride at 0° C. After stirring for 5 minutes at 0° C., the mixturewas heated at 55° C. for 1.75 hours under nitrogen. The mixture wascooled to 0° C. and used without purification. 4-Fluoroaniline (3.1 mL,32.8 mmol) in tetrahydrofuran (10 mL) was added to acetic-formicanhydride (12.5 mL, 88 mmol) at 0° C. The reaction was stirred for 25minutes and the volatiles were removed under vacuum to provide theformamide as a brown solid. A portion of the crude solid (2.39 g, 17.2mmol) was dissolved in tetrahydrofuran (8 mL) and cooled to 0° C. Boranein tetrahydrofuran (40 mL of a 1.0M solution) was added dropwise. Gasevolution was evident during the first half of the addition. After theaddition, the solution was heated to reflux for 3 hours. The solutionwas cooled to 0° C. and methanol (10 mL) was added carefully. Afterstirring for 10 minutes, ethanolic hydrogen chloride (7 mL of a 7.1Msolution) was added and the reaction was stirred overnight. Afterremoval of all volatiles in vacuo, crude N-methyl-4-fluoroaniline wasobtained as a light purple solid. NMR (200 MHz, DMSO-d₆): δ 2.65 (s,3H); 5.54 (s, 1H); 6.51 (dd, J₁ =4.7 Hz, J₂ =8.8 Hz, 2H); 6.93 (dd, J₁=8.9 Hz, J₂ =8.8 Hz, 2H).

3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoylchloride (Example 9, infra, 2.08 g. crude, approximately 1.29 g actualcompound, 2.51 mmol based on3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-benzoicacid) was dissolved in 8 mL of dichloromethane at room temperature undernitrogen. Triethylamine (0.5 mL) was added to the solution. Then4-fluoro-N-methylaniline (0.478 mg, 3.82 mmol) in dichloromethane (5 mL)was added dropwise to the solution (exothermic), and the reaction wasstirred overnight at room temperature. All volatiles were removed byevaporation under reduced pressure to provide a gummy yellow-brownsolid.

The crude solid was dissolved in acetonitrile (8 mL) under nitrogen atroom temperature. Tetraethylammonium fluoride hydrate (1.06 g, 5.7 mmol)was added and the solution was stirred overnight at room temperature.After removal of solvent, the residue was purified by chromatography onsilica gel (4 cm×14 cm) with 0.25-3.5% ethanol in dichloromethane togive 0.419 g (34% over 4 steps from3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoicacid) of(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(hydroxybenzyl)-N-(4-fluorophenyl)-N-methyl-benzamideas a yellow powder. NMR (300 MHz, DMSO-d₆): δ 0.88 (d, J=6.0 Hz , 3H);0.96 (d, J=6.0 Hz, 3H); 1.68 (dd, J₁ =7.7 Hz, J₂ =10.8 Hz, 1H); 2.02(dd, J₁ =7.1 Hz, J₂ =10.7 Hz, 1H); 2.28 (br d, J=10.7 Hz, 1H); 2.35-2.52(m, 2H); 2.66 (br d, J=10.6 Hz, 1H); 2.82 (dd, J₁ =7.4 Hz, J₂ =13.9 Hz,1H); 3.16 (dd, J₁ =4.6 Hz, J₂ =14.0 Hz, 1H); 3.32 (s, 3H); 4.77 (s, 1H);5.10 (d, J=10.3 Hz, 1H); 5.16 (d, J=17.3 Hz, 1H); 5.70-5.84 (m, 1H);6.43 (d, J=7.4 Hz, 1H); 6.56 (s, 1H); 6.64 (d, J=8.0 Hz, 1H); 7.02-7.22(m, 9H); 9.31 (s, 1H). Mass spectrum CI--CH₄) m/e: 488 (M+1, 100%), 334(11%), 153 (68%). α!_(D) ²⁰ =+6.9° (ethanol, c=1.6). The free amine(0.390 g) was dissolved in ethanol and titrated with ethanolic hydrogenchloride to pH 3.3 followed by precipitation with diethyl ether fromdichloromethane to give 0.327 g (78% recovery) of the monohydrochloridesalt as a hygroscopic light yellow powder. Calc. for C₃₀ H₃₄ N₃ O₂ F HClH₂ O: C, 66.47; H, 6.88; N, 7.75; F, 3.50; Cl, 6.54. Found: C, 66.36; H,6.74; N, 7.82; F, 3.27; Cl, 6.62.

EXAMPLE 11 (+)-3-((α,R)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-chlorophenyl)-N-methylbenzamide

4-Chloro-N-methylaniline was prepared from 4-chloroaniline, coupled with3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoylchloride, deprotected and purified by the methods described in Example10 to give(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-chlorophenyl)-N-methylbenzamideas a light yellow powder. NMR (300 MHz, DMSO-d₆): δ 0.89 (d, J=6.2 Hz,3H); 0.96 (d, J=6.1 Hz, 3H); 1.65 (dd, J₁ =7.6 Hz, J₂ =10.8 Hz, 1H);2.01 (dd, J=6.2 Hz, J₂ =10.4 Hz, 1H); 2.27 (dd, J₁ =1.5 Hz, J₂ =11.4 Hz,1H); 2.35-2.52 (m, 2H); 2.65 (br d, J=10.8 Hz, 1H); 2.82 (dd, J₁ =7.6Hz, J₂ =13.5 Hz, 1H); 3.16 (dd, J₁ =4.5 Hz, J₂ =14.6 Hz, 1H); 3.33 (s,3H); 4.77 (s, 1H); 5.10 (d, J=10.2 Hz, 1H); 5.16 (d, J=17.2 Hz, 1H);5.70-5.86 (m, 1H); 6.42 (d, J=8.1 Hz, 1H); 6.56 (s, 1H); 6.64 (d, J=7.5Hz, 1H); 7.04-7.25 (m, 5H); 7.13 (d, J=8.5 Hz, 2H); 7.29 (d, J=8.5 Hz,2H); 9.31 (s, 1H). Mass spectrum (CI--CH₄) m/e: 504 (³⁵ Cl, M+1, 86%),350 (28%), 153 (100%). α!_(D) ²⁰ =+10.2° (ethanol, c=1.6). Themonohydrochloride salt was prepared as in Example 10 to give ahygroscopic light-yellow powder. Calc. for C₃₀ H₃₄ N₃ O₂ Cl HCl 0.75H₂O: C, 65.04; H, 6.64; N, 7.58; Cl, 12.80. Found: C, 65.04; H, 6.71; N,7.49; C, 12.83.

EXAMPLE 12(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-phenylbenzamide

3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoylchloride (Example 9, infra, 2.81 g crude, approximately 1.74 g. actualcompound, 3.39 mmol based on3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoicacid) was dissolved in 10 mL of dichloromethane at room temperatureunder nitrogen. Triethylamine (0.5 mL) was added to the solution. ThenN-ethylaniline (0.780 mL, 6.2 mmol) was added dropwise to the solution(exothermic), and the reaction was stirred overnight at roomtemperature. All volatiles were removed by evaporation under reducedpressure to provide a thick brown oil.

The crude oil was dissolved in acetonitrile (10 mL) under nitrogen atroom temperature. Tetraethylammonium fluoride hydrate (1.5 g, 8.1 mmol)was added and the solution was stirred for 1 hour at room temperature.After removal of solvent, the residue was purified by chromatography onsilica gel (4 cm×15 cm) with 0.5-3% ethanol in dichloromethane to give0.508 g (31% over 4 steps from3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoicacid) of(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-phenylbenzamideas a white solid. NMR (300 MHz, DMSO-d₆): δ 0.89 (d, J=6.1 Hz, 3H); 0.96(d, J=6.1 Hz, 3H); 1.07 (t, J=7.0 Hz, 3H); 1.67 (dd, J₁ =7.4 Hz, J₂=10.4 Hz, 1H); 2.02 (dd, J₁ =7.4 Hz, J₂ =10.6 Hz, 1H); 2.27 (dd, J₁ =1.4Hz, J₂ =10.6 Hz, 1H); 2.36-2.52 (m, 2H); 2.66 (br d, J=10.4 Hz, 1H);2.82 (dd, J₁ =7.8 Hz, J₂ =13.5 Hz, 1H); 3.16 (dd, J₁ =4.0 Hz, J₂ =13.9Hz, 1H); 3.83 (q, J=7.0 Hz, 2H); 4.75 (s, 1H); 5.09 (d, J=9.9 Hz, 1H);5.16 (d, J=17.2 Hz, 1H); 5.70-5.84 (m, 1H); 6.41 (d, J=7.6 Hz, 1H); 6.54(s, 1H); 6.63 (d, J=8.2 Hz, 1H); 7.03-7.29 (m, 10H); 9.30 (s, 1H). Massspectrum (CI--CH₄) m/e: 484 (M+1, 100%), 330 (57%), 153 (66%). α!_(D) ²⁰=+10.4° (ethanol, c=1.2). The monohydrochloride salt was prepared from0.473 g of the free amine as in Example 10 to give 0.389 g (76%recovery) of a hygroscopic white powder. Calc. for C₂₇ H₃₇ N₃ O₂ HCl H₂O: C, 69.19; H, 7.49; N, 7.81; Cl, 6.59. Found: C, 69.41; H, 7.52; N,7.73; Cl, 6.48.

EXAMPLE 13(-)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-phenylbenzamide

This compound was obtained as a light yellow powder from aniline and3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(t-butyl-dimethylsilyloxy)benzyl)benzoylchloride (Example 9, infra) using the Benzamide-Formation Methoddescribed in Example 9. NMR (200 MHz, DMSO-d₆): δ 0.99 (d , J=5.7 Hz,3H); 1.10 (d, J=5.8 Hz, 3H); 1.91 (dd, J₁ =7.0 Hz, J₂ =10.5 Hz, 1H);2.14 (dd, J₁ =6.0 Hz, J₂ =10.4 Hz, 1H); 2.51-2.81 (m, 4H); 2.88 (dd, J₁=6.8 Hz, J₂ =13.9 Hz, 1H); 3.18 (dd, J₁ =5.4 Hz, J₂ =13.8 Hz, 1H); 5.06(d, J=15.6 Hz, 1H); 5.14 (s, 1H); 5.19 (d, J=18.1 Hz, 1H); 5.75 (m, 1H);6.73 (m, 3H); 7.10 (d, J=7.8 Hz, 1H); 7.17 (d, J=8.0 Hz, 1H); 7.30-7.59(m, 3H); 7.65 (d, J=7.6 Hz, 1H); 7.71-7.83 (m, 3H); 7.93 (s, 1H); 9.37(s, 1H); 10.21 (s, 1H). Mass spectrum (CI--CH₄) m/e: 456 (M+1, 100%),302 (41%), 153 (77%). α!_(D) ²⁰ =-4.44° (ethanol, c=1.4). Themonohydrochloride salt was prepared as in Example 9 to give ahygroscopic light yellow powder. Calc. for C₂₉ H₃₃ N₃ O₂ HCl 0.75 H₂ O:C, 68.90 H, 7.08; N, 8.31; Cl, 7.01. Found: C, 69.00; H, 7.06; N, 8.32;Cl, 6.95.

EXAMPLE 14(+)-3-((αR)-α-(2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-(2-pyridyl)benzamide

2-(Methylamino)pyridine was prepared from 2-aminopyridine, coupled with3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoylchloride, deprotected and purified by the methods described in Example10 to give(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-(2-pyridyl)benzamideas a light yellow powder. NMR (200 MHz, DMSO-d₆): δ 0.90 (d, J=6.1Hz,3H); 0.98 (d, J=5.9 Hz, 3H); 1.70 (dd, J₁ =6.8Hz, J₂ =10.7 Hz, 1H); 2.02(dd, J₁ =7.5 Hz, J₂ =11.6 Hz, 1H); 2.30 (br. d, J=10.7 Hz, 1H);2.38-2.57 (m, 2H); 2.66 (dd, J₁ =2.6 Hz, J₂ =11.8 Hz, 1H); 2.81 (dd, J₁=6.5 Hz, J₂ =14.5 Hz, 1H); 3.18 (br. d, J=14.4 Hz, 1H); 3.41 (s, 3H);4.81 (s, 1H); 5.10(d, J=10.2 Hz, 1H); 5.17 (d, J=17.1 Hz, 1H); 5.69-5.88(m, 1H); 6.43 (d, J=7.6 Hz, 1H); 6.54 (s, 1H); 6.65 (dd, J₁ =1.7, J₂=8.2 Hz, 1H); 6.95-7.32 (m, 7H); 7.64 (td, J₁ =1.8 Hz, J₂ =7.7 Hz, 1H);8.35 (dd, J₁ =1.3 Hz, J₂ =4.9 Hz, 1H); 9.33 (s, 1H). Mass spectrum(CI--CH₄) m/e: 471 (M+1, 100%), 317 (59%), 153 (88%). α!_(D) ²⁰ =+12.0°(ethanol, c=1.3). The free amine was dissolved in ethanol and titratedwith ethanolic hydrogen chloride to pH 3.2, followed by precipitationwith diethyl ether from dichloromethane to give the monohydrochloridesalt as a hygroscopic light yellow powder. Calc. for C₂₉ H₃₄ N₄ O₂ HClH₂ O: C, 66.33; H, 7.10; N, 10.67; Cl, 6.75. Found: C, 66.58; H, 7.32;N, 10.41; Cl, 6.80.

EXAMPLE 15(+)-3-((αR)-α-((2R,5S)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-(((benzyloxy)carbonyl)amino)benzyl)phenol

3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoylchloride (Example 9, infra, 1.8 g. crude, approximately 1.12 g. actualcompound, 2.18 mmol) was dissolved in 75 mL of acetone and chilled to 0°C. under nitrogen. A solution of sodium azide (1.14 g, 17.5 mmol) in 12mL of water was added slowly to the mixture. The reaction was stirred at0° C. for 0.75 hour (with appropriate safety shield) and then warmed toroom temperature and stirred for 1.5 hours. The reaction mixture wasdiluted with 30 mL of water and the acetone was removed in vacuo. Theaqueous solution was basified to pH 8 with 1M sodium hydroxide and theacyl azide was extracted with 200 mL diethyl ether. The ether extractwas diluted with 75 mL toluene, and the solution volume was concentratedto 50 mL. Benzyl alcohol (0.726 mL, 7.0 mmol) was added, and thereaction was heated at reflux overnight. The solvent was removed invacuo to give a thick brown oil.

The crude oil and tetraethylammonium fluoride hydrate (0.97 g, 5.25mmol) were stirred in 30 mL of acetonitrile for 0.5 hour. The solventwas removed, and the residue was purified by chromatography on a silicagel column (4 cm×17 cm) with ethanol (0-3.5%) in dichloromethane toprovide 0.321 g (31% from3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoicacid) of(+)-3-((αR)-α((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(((benzyloxy)-carbonyl)amino)benzyl)phenol as a light yellow solid. NMR (200 MHz, DMSO-d₆): δ 0.97 (d, J=5.9Hz, 3H); 1.07 (d, J=6.1 Hz, 3H), 1.72-1.93 (m, 2H); 2.10 (dd, J₁ =6.7Hz, J₂ =10.5 Hz, 1H); 2.56-2.92 (m, 3H); 3.18 (dd, J₁ =5.1 Hz, J₂ =14.2Hz, 1H); 3.63 (m, 1H); 4.86 (s, 1H); 5.06-5.26 (m, 4H); 5.70-5.91 (m,1H); 6.61-6.78 (m, 3H); 7.03 (d, J=7.0 Hz, 1H); 7.15 (m, 1H); 7.21 (d,J=7.8 Hz, 1H); 7.31-7.53 (m, 6H); 7.57 (s, 1H); 9.32 (s, 1H); 9.73 (s,1H). Mass spectrum (CI--CH₄) m/e: 486 (M+1,69%), 332 (64%), 153 (100%).α!_(D) ²⁰ =+16.9° (ethanol, c=1.1). The free amine (0.301 g) wasdissolved in ethanol and titrated with ethanolic hydrogen chloride to pH3.1, followed by precipitation with diethyl ether from dichloromethaneto give 0.262 g (81% recovery) of the monohydrochloride salt as ahygroscopic light yellow powder. Calc. for C₃₀ H₃₅ N₃ O₃ HCl 0.5 H₂ O:C, 67.85, H, 7.02; N, 7.91; Cl, 6.68. Found: C, 67.65; H, 7.07; N, 7.77;Cl, 6.45.

EXAMPLE 16 (+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide

Method A

3-Fluoro-N-methylaniline NMR (200 MHz, DMSO-d₆): δ 2.76 (s, 3H); 3.42(s, 1H); 6.51-6.92 (m, 3H); 7.28 (dt, J₁ =7.3 Hz, J₂ =8.0 Hz, 1H)! wasprepared from 3-fluoroaniline, coupled with3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethyl-silyloxy)benzyl)benzoylchloride, deprotected and purified by the methods described in Example10 to give(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamideas a light yellow powder. NMR (200 MHz, DMSO-d₆): δ 0.84 (d, J=6.0 Hz,3H); 0.97 (d, J=5.9 Hz, 3H); 1.69 (dd, J₁ =7.7 Hz, J₂ =10.7 Hz, 1H);2.01 (dd, J₁ =7.4 Hz, J₂ =10.7 Hz, 1H); 2.28 (br d, J=8.3 Hz, 1H);2.40-2.52 (m, 2H); 2.67 (br d, J=10.5 Hz, 1H); 2.82 (dd, J₁ =7.6 Hz, J₂=13.2 Hz, 1H); 3.17 (br d, J=14.0 Hz, 1H); 3.34 (s, 3H); 4.80 (s, 1H);5.10 (d, J=10.1 Hz, 1H); 5.17 (d, J=17.3 Hz, 1H); 5.70-5.84 (m, 1H);6.42 (d, J=7.1 Hz, 1H); 6.56 (s, 1H); 6.65 (d, J=8.3 Hz, 1H); 6.90-7.32(m, 9H); 9.31 (s, 1H). Mass spectrum (CI--CH₄) m/e: 488 (M+1, 100%), 334(39%), 153 (87%). α!_(D) ²⁰ =+4.9° (ethanol, c=1.2). The free amine(0.091 g) was dissolved in ethanol and titrated with ethanolic hydrogenchloride to pH 3.7 followed by precipitation with diethyl ether fromdichloromethane to give 0.072 g (74% recovery) of the monohydrochloridesalt as a hygroscopic light yellow powder. Calc. for C₃₀ H₃₄ N₃ O₂ F HCl1.25 H₂ O: C, 65.92 H, 6.92; N, 7.69; Cl, 6.49. Found: C, 66.07; H,6.95; N, 7.53; Cl, 6.54.

Method B

3-Fluoro-N-methylaniline was prepared from 3-fluoroaniline using amodified reductive amination. First, 1-hydroxymethylbenzotriazole wasprepared by adding 37% aqueous formaldehyde to benzotriazole at 40° C.in a 1:1 ratio and cooling to room temperature to precipitate theproduct. After filtration the hydroxymethylbenzotriazole (125 g) washeated to reflux in toluene with 3-fluoroaniline (92.2 g). Water wasremoved azeotropically using a Dean-Stark trap. After three hours, themixture was cooled to room temperature, then refrigerated for severalhours to complete precipitation. The white crystalline solid wascollected by filtration, yielding 174.2 g (86.6%) of1-((3-fluoroanilino)methyl)-1H-benzotriazole.

1-((3-Fluoroanilino)methyl)-1H-benzotriazole (173.9 g) was slurried indry tetrahydrofuran. Sodium borohydride (32.5 g) was added portionwiseto the mixture at room temperature. After addition was complete, themixture was heated at reflux for 4 hours. The solution was cooled andpoured slowly into 400 mL of 5M hydrochloric acid with ice and stirredfor 1 hour at room temperature. The solution pH was adjusted to 9-10using 10M sodium hydroxide solution. The product was extracted usingdiethyl ether. The ether extracts were washed successively with 1Msodium hydroxide solution, saturated sodium chloride solution, andwater. The organic phase was dried over sodium sulfate and evaporatedunder reduced pressure to yield 87.5 g (97%) of 3-fluoro-N-methylanilineas a colorless oil. NMR (200 MHz, DMSO-d₆): δ 2.76 (s, 3H); 3.41 (br s,1H); 6.59-6.92 (m, 3H); 7.27 (q, J=8.0Hz, 1H)!.

3-Carboxybenzaldehyde (Alfrebro Inc., Monroe, Ohio; 2.0 g.) was slurriedin thionyl chloride (6 mL). A reflux condenser fitted with a calciumchloride drying tube was placed on the flask. The reaction was placed inan oil bath and heated at a bath temperature maintained below 100° C.The mixture was allowed to reflux until a clear solution was obtainedand for 5-10 additional minutes before cooling to room temperature. Thesolution was diluted with anhydrous toluene, and all volatiles wereremoved under vacuum.

The crude acid chloride was dissolved in dichloromethane and cooled inan ice/water bath. Triethylamine (6 mL) was added dropwise via anaddition funnel, followed by N-methyl-3-fluoroaniline (1.83 g) indichloromethane. The cloudy solution was allowed to warm to roomtemperature over 1 hour. Water was added and the product was extractedwith dichloromethane. The organic layer was washed with water andsaturated sodium chloride solution and dried over sodium sulfate, andthe solvent was removed under vacuum.N-(3-Fluorophenyl)-3-formyl-N-methylbenzamide (3.20 g) was obtained as alight golden oil (93% unchromatographed yield). NMR (300 MHz, DMSO-d₆):δ 3.38 (s, 3H); 6.94-7.02 (m, 2H); 7.18-7.29 (m, 2H); 7.46 (t, J=7.7 Hz,1H) 7.55 (d, J=7.6 Hz, 1H); 7.81 (m, 2H); 9.90 (s, 1H)!.

A 12 L, 3-necked round bottom flask was charged withtrans-2,5-dimethylpiperazine (767 g, 6.72 mol), which had beenrecrystallized from toluene to mp=115-119° C., and 600 mL of water. Theflask was cooled in an ice bath and a solution of methanesulfonic acid(1290 g, 13.4 mol) in 600 mL of water was added slowly with stirring andcooling to maintain the temperature below 40° C. The solution was cooledto 20° C. and 800 mL of ethanol was added. A 500 mL addition funnel wasfilled with 60% aqueous potassium acetate from a 2 L reservoir of thesolution, and potassium acetate was added to the reaction flask toadjust the pH to 4.0. A second addition funnel was charged with asolution of ethyl chloroformate (642 mL, 6.71 mol) in 360 mL oftetrahydrofuran. The ethyl chloroformate and potassium acetate solutionswere simultaneously added dropwise with adjustment of rate to maintainthe reaction solution at pH 4.0±0.1, with cooling as necessary tomaintain temperature at 25° C. After addition of the ethyl chloroformatewas complete, the reaction was stirred for 1 hour with continuedaddition of potassium acetate solution to maintain a pH of 4.0. Theorganic solvents were removed by distillation under vacuum. Theremaining aqueous solution was washed with 1500 mL of ethyl acetate toremove any bis-carbamate impurity. The ethyl acetate wash was extractedwith two 500 mL portions of 1M hydrochloric acid to recover desiredproduct. The acid extracts were combined with the original aqueoussolution and the pH was adjusted to 11 by addition of 10M sodiumhydroxide, with cooling to maintain temperature below 40° C. The aqueoussolution was extracted with two 1500 mL portions of ethyl acetate, thecombined extracts were dried over magnesium sulfate, and the solvent wasremoved to give 927 g (74%) ethyltrans-2,5-dimethyl-1-piperazinecarboxylate as a yellow oil.

A mixture of ethyl trans-2,5-dimethyl-1-piperazinecarboxylate (643 g,3.45 mol), allyl bromide (328 mL, 3.80 mol), and sodium carbonate (440g, 4.15 mol) in 2500 mL of acetonitrile was heated at reflux for 1.5hours. The reaction was cooled to room temperature, filtered, and thesolvent removed under vacuum. The residue was dissolved in 4000 mL ofdichloromethane and washed with two 500 mL portions of 1M sodiumhydroxide. The dichloromethane solution was dried over magnesium sulfateand the solvent was removed to give 630 g (81%) of ethyltrans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate as an oil. Ethyltrans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate (630 g, 2.78 mol) wasadded to a solution of 87% potassium hydroxide pellets (2970 g, 46 mol)in 4300 mL of 95% ethanol and heated at reflux for 1.5 hours. Carbondioxide evolution was observed for the first 0.5-1 hour of heating. Thereaction was cooled below reflux temperature and 2000 mL of toluene wascarefully added. Ethanol was removed by azeotropic distillation at 105°C., while adding an additional 4000 mL of toluene to the reaction flaskduring the course of the distillation. After collection of 9000 mL ofdistillate, the reaction was cooled to 100° C. and 1000 mL of toluenewas carefully added. The solution was slowly cooled to 5° C. andmaintained at 5° C. for 30 minutes. The solution was filtered, and thefilter cake was washed with an additional 1500 mL of toluene. Thefiltrate was washed with 1000 mL of water, dried over magnesium sulfate,and the solvent was removed to give 296 g (69%) oftrans-1-allyl-2,5-dimethylpiperazine as a dark liquid. NMR (300 MHz,DMSO-d₆): δ 0.87 (d, J=6.3 Hz, 3H); 0.92 (d, J=6.3 Hz, 3H); 1.63 (t,J=11 Hz, 1H); 2.05 (m, 1H); 2.30 (t, J=11 Hz, 1H); 2.6-2.8 (m, 4H); 3.33(dd, J₁ =5 Hz, J₂ =14 Hz, 1H); 5.09 (d, J=8.7 Hz, 1H); 5.13 (d, J=14 Hz,1H) 5.8 (m, 1H).

Di-p-toluoyl-D-tartaric acid (Schweizerhall, Inc., South Plainfield,N.J.) (1.25 Kg, 3.2 mol) was dissolved in hot (˜60° C.) 95% ethanol (16L) and racemic trans-1-allyl-2,5-dimethylpiperazine (500 g, 3.2 mol) wasadded in several portions (caution: exothermic). The hot solution wasseeded with crystals of the diastereoisomerically pure salt (obtainedfrom a previous small-scale resolution) and cooled to room temperatureover 2-3 hours. The solution was slowly stirred for 2 days at roomtemperature. The resulting salt was collected by filtration, washedtwice with 95% ethanol, and dried under vacuum to give 826.5 g of awhite solid (47%). The process was repeated with a second batch of thedi-p-toluoyl-D-tartaric acid and racemictrans-1-allyl-2,5-dimethylpiperazine to give 869 g (50%).

The total of 1695 g of salt was divided into three batches and eachbatch was recrystallized twice in the following fashion. The salt wasdissolved in refluxing 95% ethanol (˜2.7 L/100 g of salt), andapproximately half of the ethanol was removed by distillation. (Note:vigorous stirring was necessary during distillation to preventcrystallization on the vessel wall.) The hot solution was seeded withcrystals of the pure diastereomeric salt, cooled to room temperature,and stirred slowly for 2 days before collecting the salt by filtration.(Note: a subsequent experiment suggested that crystallization time canbe reduced from 2 days to 8 hours.) The total amount recovered was 1151g. The salt was dissolved in 3 L of 2M aqueous sodium hydroxide, and theaqueous solution was extracted with four 1 L portions ofdichloromethane. The organic extracts were combined, dried over sodiumsulfate, and solvent removed by rotary evaporation (temperature <20° C.)to give 293 g (29% based on racemic weight) of(2R,5S)-1-allyl-2,5-dimethylpiperazine as a clear oil. α!_(D) ²⁰ =-55.1°(abs. ethanol, c=1.2). The trifluoroacetamide of the product wasprepared with trifluoroacetic anhydride and analyzed by chiral capillarygas chromatography (Chiraldex B-PH column, 20 m×0.32 mm, AdvancedSeparation Technologies Inc., Whippany, N.J., 120° C.) indicating anenantiopurity of 99% ee (retention time of desired enantiomer, 11.7 min;other enantiomer, 10.7 min).

(2R,5S)-1-allyl-2,5-dimethylpiperazine (6.13 g), benzotriazole (4.79 g),and N-(3-fluorophenyl)-3-formyl-N-methylbenzamide (10.23 g) were mixedin dry toluene with one drop of triethylamine. The mixture was placed inan oil bath maintained at 140° C. (bath temperature). The flask wasattached to a Dean-Stark trap to allow the azeotropic removal of water,under a stream of nitrogen. The mixture was heated at reflux for 2-3hours and most of the toluene was removed under reduced pressure. Thecrude adduct may be isolated by crystallization at this stage to give3-(((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(1H-benzotriazol-1yl)methyl)-N-(3-fluorophenyl)-N-methylbenzamideas a mixture of epimers, but due to the water-sensitive nature of theadduct, it is generally easier to use the crude material for subsequentreactions. (The reaction mixture in toluene is usually satisfactory forthe next step.)

A solution of 3-bromophenol (500 g, 2.89 mol),tert-butylchlorodimethylsilane (436 g, 2.89 mol), and imidazole (500 g,7.22 mol) in 500 mL of dimethylformamide was stirred overnight at roomtemperature. The reaction solution was poured into 3000 mL of water andextracted with two 2000 mL portions of diethyl ether. The combined etherextracts were dried over sodium sulfate and the solvent removed to give846 g of 3-(bromophenoxy)-tert-butyldimethylsilane as a pale yellowliquid. NMR (300 MHz, CDCl₃): δ 0.2 (s, 6H); 1.0 (s, 9H); 6.75 (m, 1H);7.0 (br s, 1H); 7.1 (m, 2H).

3-(Bromophenoxy)-tert-butyldimethylsilane (17.12 g) was dissolved in drytetrahydrofuran (150 mL), and cooled to -78° C. under nitrogen.n-Butyllithium in hexanes (23.88 mL of a 2.5M solution) was added slowlyvia syringe to the solution. While stirring for 40 minutes at -78° C.,the solution became white and somewhat thick. The solution wastransferred via a double-ended needle to a flask containing magnesiumbromide etherate (16.5 g) in tetrahydrofuran (150 mL) and stirred for 1hour at room temperature. The crude benzothiazole adduct from abovecontaining primarily3-(((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(1H-benzotriazol-1-yl)methyl)-N-(3-fluorophenyl)-N-methylbenzamidewas dissolved in tetrahydrofuran and added to the arylmagnesium bromidereagent just prepared. The solution waned slightly during the additionand became a cloudy yellow-brown color. After stirring at roomtemperature for 2 hours, 0.5 M aqueous hydrochloric acid was addedcautiously until the solution reached pH=6. The product was extractedwith 250 mL of ethyl acetate and the solvent was removed under vacuum.

The tert-butyldimethylsilyl protecting group was removed by dissolvingthe residue in 175 mL of tetrahydrofuran and adding 85 mL of 3N aqueousHCl at room temperature. The solution warmed upon acid addition. Themixture was stirred for 40 minutes at room temperature. Diethyl etherwas added, and the acidic aqueous layer was separated. The aqueous layerwas washed a second time with diethyl ether and adjusted to pH=8-9 usingaqueous sodium hydroxide solution. The product was extracted using ethylacetate. The ethyl acetate portions were combined, and washed withdilute sodium hydroxide solution to remove any remaining benzotriazole.The organic layer was then washed with saturated sodium chloridesolution, dried over sodium sulfate, and evaporated under reducedpressure. The product (10.85 g, 56%) was recovered as a mixture of twodiastereomers in a 91:9 ratio favoring the desired diastereomer, asdetermined by HPLC analysis. HPLC was performed on a μ-Bondapak C-18column (125 Å, 3.9×300 nm, Waters Chromatography Division, MilliporeCorporation, Milford, Mass.) using 60% methanol and 40% 0.1M aqueousammonium acetate at a flow rate of 1 mL/min. The diastereomeric mixturewas recrystallized from ethyl acetate/hexane to give(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamideas a white crystalline solid (mp 144-145° C.) in 99% isomeric purity (asdetermined by HPLC). NMR (200 MHz, DMSO-d₆): δ 0.84 (d, J=6.0 Hz, 3H);0.97 (d, J=5.9 Hz, 3H); 1.69 (dd, J₁ =7.7 Hz, J₂ =10.7 Hz, 1H); 2.01(dd, J₁ =7.4 Hz, J₂ =10.7 Hz, 1H); 2.28 (br d, J=8.3 Hz, 1H); 2.40-2.52(m, 2H); 2.67 (br d, J=10.5 Hz, 1H); 2.82 (dd, J₁ =7.6 Hz, J₂ =13.2 Hz,1H); 3.17 (br d, J=14.0 Hz, 1H); 3.34 (s, 3H); 4.80 (s, 1H); 5.10 (d,J=10.1 Hz, 1H); 5.17 (d, J=17.3 Hz, 1); 5.70-5.84 (m, 1H); 6.42 (d,J=7.1 Hz, 1H); 6.56 (s, 1H); 6.65 (d, J=8.3 Hz, 1H); 6.90-7.32 (m, 9H);9.31 (s, 1H). Mass spectrum (CI--CH₄) m/e: 488 (M+₁, 100%), 334 (39%),153 (87%). α!_(D) ²⁰ =+5.4° (abs. ethanol, c=1.4). Calc. for C₃₀ H₃₄ FN₃O₂ : C, 73.90; H, 7.03; N, 8.62. Found: C, 73.86; H, 7.02; N, 8.53. Themonohydrochloride salt may be formed as in Method A.

EXAMPLE 173-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-(2,4,6-trichlorophenyl)benzamide

N-Methyl-2,4,6-trichloroaniline NMR (200 MHz, CDCl₃): δ 2.82 (s, 3H);5.11 (s, 1H); 7.46 (s, 2H)! was prepared from 2,4,6-trichloroaniline,coupled with 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoylchloride, deprotected and purified by the methods described in Example10 to give(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-(2,4,6-trichlorophenyl)benzamideas an off-white powder. NMR (200 MHz, DMSO-d₆): δ 0.90 (d, J=6.1 Hz,3H); 0.98 (d, J=6.0 Hz, 3H); 1.65 (dd, J₁ =7.4 Hz, J₂ =10.6 Hz, 1H);2.03 (dd, J₁ =7.5 Hz, J₂ =10.2 Hz, 1H); 2.35 (d, J=11.7 Hz, 1H);2.38-2.51 (m, 2H); 2.65 (br d, J=10.6 Hz, 1H); 2.80 (dd, J₁ =7.0 Hz, J₂=13.3 Hz, 1H); 3.12 (m, 1H); 3.18 (s, 3H); 4.80 (s, 1H); 5.11 (d, J=11.0Hz, 1H); 5.18 (d, J=16.8 Hz, 1H); 5.66-5.87 (m, 1H); 6.48 (d, J=8.4 Hz,1H); 6.56 (s, 1H); 6.64 (d, J=8.6 Hz, 1H); 7.16 (t, J=8.0, 1H);7.22-7.28 (m, 3H); 7.38 (s, 1H); 7.69 (d, J=2.2 Hz, 1H); 7.72 (d, J=2.2Hz, 1H); 9.31 (s, 1H). Mass spectrum (CI--CH₄) m/e: 572 (M+1, 14%), 153(100%).

EXAMPLE 183-(((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-(2-(trifluoromethyl)phenyl)benzamide

N-Methyl-2-(trifluoromethyl)aniline NMR (200 MHz, DMSO-d₆): δ 2.75 (s,3H); 3.40 (s, 1H); 6.70 (t, J=8.0 Hz, 1H); 6.94-7.16 (br, m, 2H); 7.38(d, J=7.3 Hz, 1H)! was prepared from 2-(trifluoromethyl)aniline, coupledwith3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoylchloride, deprotected and purified by the methods described in Example10 to give(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-(2-(trifluoromethyl)phenyl)benzamideas a yellow powder. NMR (200 MHz, DMSO-d₆): δ 0.90 (d, J=6.0 Hz, 3H);0.97 (d, J=6.0 Hz, 3H); 1.64 (m, 1H); 2.05 (m, 1H); 2.27 (br d, J=10.5Hz, 1H); 2.40-2.84 (m, 4H); 3.18 (br d, J=13.5 Hz, 1H); 3.29 (s, 3H);4.79 (s, 1H); 5.11 (d, J=10.2 Hz, 1H); 5.18 (d, J=17.0 Hz, 1H);5.70-5.82 (m, 1H); 6.42 (d, J=7.6 Hz, 1H); 6.65 (d, J=7.7 Hz, 1H); 6.67(s, 1H); 7.04-7.83 (m, 9H); 9.32 (s, 1H). Mass spectrum (CI--CH₄) m/e:538 (M+1, 82%), 384 (13%), 153 (100%).

EXAMPLE 19 (+)-3-((αR)-α-((2S,5R)-4-Allyl-1-2,5-dimethyl-1-piperazinyl)-3-(hydroxybenzyl)-N-methyl-N-(3-pyridyl)benzamide

3-(Methylamino)pyridine NMR (200 MHz, CDCl₃): δ 2.80 (s, 3H); 3.90 (s,1H); 6.83 (d, J=8.2 Hz, 1H); 7.06 (dd, J₁ =4.7 Hz, J₂ =8.2 Hz, 1H); 7.91(d, J=4.7 Hz, 1H); 7.99 (s, 1H)! was prepared from 3-aminopyridine,coupled with3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoylchloride, deprotected and purified by the methods described in Example10 to give(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-(3-pyridyl)benzamideas a light yellow powder. NMR (200 MHz, DMSO-d₆): δ 0.90 (d, J=6.1 Hz,3H); 0.99 (d, J=6.3 Hz, 3H); 1.71 (m, 1H); 2.03 (m, 1H); 2.30 (br d,J=10.4 Hz, 1H); 2.42-2.94 (m, 4H); J=13.3 Hz, 1H); 3.39 (s, 3H); 4.82(s, 1H); 5.12 (d, J=9.9 Hz, 1H); 5.18 (d, J=17.0 Hz, 1H); 5.70-5.86 (m,1H); 6.44 (d, J=7.7 Hz, 1H); 6.56 (s, 1H); 6.66 (d, J=8.8 Hz, 1H); 7.13(t, J=8.1 Hz, 1H); 7.18-7.41 (m, 5H); 7.64 (dd, J₁ =1.4 Hz, J₂ =8.1 Hz,1H); 8.29 (s, 1H); 8.34 (d, J=4.5 Hz, 1H); 9.34 (s, 1H). α!_(D) ²⁰=+11.8° (abs. ethanol, c=1.0).

EXAMPLE 20(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-benzyl-N-methylbenzamide

This compound was prepared from3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoylchloride and N-benzyl-N-methylamine by the Benzamide Formation Methoddescribed in Example 9. NMR (300 MHz, DMSO-d₆, 121° C.): δ 0.93 (d,J=6.2 Hz, 3H); 1.06 (d, J=6.2 Hz, 3H); 1.96 (dd, J₁ =6.7 Hz, J₂ =11.0Hz, 1H); 2.12 (dd, J₁ =7.0 Hz, J₂ =11.0 Hz, 1H); 2.58 (dd, J₁ =2.9 Hz,J₂ =11.4 Hz, 1H); 2.67-2.84 (m, 3H); 2.86 (s, 3H); 2.89 (dd, J₁ =6.6 Hz,J₂ =13.5 Hz, 1H); 3.18 (dd, J₁ 4.0 Hz, J₂ =14.1 Hz, 1H); 4.58 (s, 2H);4.98 (s, 1H); 5.08 (d, J=10.2 Hz, 1H); 5.16 (d, J=17.3 Hz, 1H);5.74-5.89 (m, 1H); 6.62-6.74 (m, 3H); 7.10 (t, J=7.8 Hz, 1H); 7.21-7.50(m, 9H); 8.76 (s, 1H). Mass spectrum (CI--CH₄) m/e: 484 (M+1,88%), 330(33%), 153 (100%). α!_(D) ²⁰ =+14.3° (ethanol, c=1.25). The free aminewas dissolved in ethanol and titrated with ethanolic hydrogen chlorideto pH 3.4 followed by precipitation with diethyl ether fromdichloromethane to give(+)-3-((αR)-α-((2S,SR)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-benzyl-N-methylbenzamidemonohydrochloride as a hygroscopic light yellow powder. Calc. for C₃₁H₃₇ N₃ O₂ HCl 0.75 H₂ O: C, 69.78; H, 7.46; N, 7.87; Cl, 6.64 Found: C,69.76; H, 7.48; N, 7.69; Cl, 6.74.

EXAMPLE 21(±)-cis-3-(α-(4-Allyl-3,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

(±)-3-(α-(3,5-Dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamidewas prepared from3-(3-((tert-butyldimethyl-silyl)oxy)-α-chlorobenzyl)-N,N-diethylbenzamide(Example 1, infra) and cis-2,6-dimethylpiperazine according to themethods of Example 1. This material was then alkylated with allylbromide and deprotected by methods similar to that in Example 4 to give(±)-cis-3-(α-(4-allyl-3,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide.NMR (DMSO-d₆, 200 MHz): δ 0.87 (d, J=3.9 Hz, 3H); 0.90 (d, J=3.9 Hz,3H); 0.940-1.22 (m, 6H); 1.65 (t, J=10.7 Hz, 2H); 2.55-2.75 (m, 4H);3.00-3.22 (m, 2H); 3.22-3.54 (m, 4H); 4.16 (s, 1H); 5.15 (dd, J₁ =2.2Hz, J₂ =10.0 Hz, 1H); 5.22 (d, J=14.8 Hz, 1H); 5.96 (m, 1H); 6.58 (d,J=8.0 Hz, 1H); 6.82 (d, J=7.3 Hz, 1H); 6.84 (s, 1H); 7.02-7.20 (m, 2H);7.30-7.46 (m, 3H); 9.33 (s, 1H). Mass spectrum (CI--CH₄) m/e: 436 (M+1,100%). The monohydrochloride salt was prepared as in Example 4. Calc.for C₂₇ H₃₇ N₃ O₂ HCl 0.75 H₂ O: C, 66.78; H, 8.20; N, 8.65; Cl, 7.30.Found: C, 66.84; H, 8.28; N, 8.53; Cl, 7.25.

EXAMPLE 22 3-((αR orαS)-α-((2S,5S)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

3-(α-((2S,5S)-2,5-Dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamidewas prepared as a mixture of epimers from3-(3-((tert-butyldimethylsilyl)oxy)-α-chlorobenzyl)-N,N-diethylbenzamide(Example 1, infra) and (+)-(2S,5S)-2,5-dimethylpiperazine prepared fromL-Ala-L-Ala-diketopiperazine (Bachem Chemicals, Philadelphia, Pa.) asdescribed by Jung and Rohloff (J. Org. Chem. 50, 4909-13 (1985))!according to the methods of Example 1. This material was then alkylatedwith allyl bromide by methods similar to that in Example 4 to give amixture of diastereomers that was separated by chromatography on silicagel (Waters Prep 500 A, 0.1% triethylamine in dichloromethane). Thefirst isomer to elute was deprotected by the method in Example 4 to give3-((αR orαS)-α-((2S,5S)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide.NMR (DMSO-d₆, 200 MHz): δ 0.890 (d, J=5.6 Hz, 3H); 0.981 (d, J=6.4 Hz,3H); 1.00-1.25 (m, 6H); 2.10-2.48 (m, 4H); 2.59 (d, J=11.1 Hz, 1H); 2.73(dd, J₁ =7.8 Hz, J₂ =14.1 Hz, 1H); 2.90-3.60 (m, 6H); 4.54 (s, 1H); 5.13(d, J=9.0 Hz, 1H); 5.19 (d, J=16.2 Hz, 1H); 5.84 (m, 1H); 6.58 (d, J=8.0Hz, 1H); 6.86 (s, 1H); 6.88 (d, J=7.1 Hz, 1H); 7.08 (t, J=7.6 Hz, 1H);7.14 (d, J=7.8 Hz, 1H); 7.34 (t, J=7.6 Hz, 1H); 7.43 (s, 1H); 7.48 (d,J=7.7 Hz, 1H); 9.32 (s, 1H).

EXAMPLE 23 3-((αS orαR)-α-((2S,5S)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

The second isomer to elute from the column of Example 22 was deprotectedin similar fashion to give the benzhydryl epimer of Example 22. NMR(DMSO-d₆, 200 MHz): δ 0.903 (d, J=5.5 Hz, 3H); 0.965 (d, J=6.5 Hz, 3H);1.00-1.20 (m, 6H); 2.16 (t, J=9.9 Hz, 1H); 2.25-2.45 (m, 3H); 2.48-2.62(m, 1H); 2.70-2.90 (m, 2H); 3.00-3.25 (m, 2H); 3.25-3.50 (m, 3H); 4.52(s, 1H); 5.12 (d, J=8.6 Hz, 1H); 5.18 (d, J=16.0 Hz, 1H); 5.82 (m, 1H);6.56 (d, J=7.0 Hz, 1H); 6.89 (d, J=7.4 Hz, 1H); 6.91 (s, 1H); 7.06 (t,J=8.0 Hz, 1H); 7.14 (d, J=7.2 Hz, 1H); 7.35 (t, J=7.4 Hz, 1H); 7.38 (s,1H); 7.49 (d, J=7.6 Hz, 1H); 9.31 (s, 1H).

EXAMPLE 24

3-((αR orαS)-α-(2R,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide,the enantiomer of Example 22, was prepared in identical fashion toExample 22 using (-)-(2R,5R)-2,5-dimethylpiperazine prepared fromD-Ala-D-Ala-diketopiperazine (Bachem Chemicals, Philadelphia, Pa.) asdescribed by Jung and Rohloff (J. Org. Chem. 50, 4909-13 (1985))!.Chromatography of the silyl-protected product provided the first isomerto elute as a yellow oil. Deprotection with tetraethylammonium fluoridegave the desired product. NMR (DMSO-d₆, 300 MHz): δ 0.85 (d, J=6 Hz,3H); 0.95 (d, J=6 Hz, 3H); 2.15 (t, J=9 Hz, 1H); 2.25 (m, 2H); 2.35 (dd,J₁ =3 Hz, J₂ =11 Hz, 1H); 2.55 (dd, J₁ =2 Hz, J₂ =11 Hz, 1H); 2.7 (q,J=7 Hz, 1H); 2.95 (m, 1H); 3.1 (br m, 2H); 3.4 (br m, 3H); 4.5 (s, 1H);5.1 (d, J=11 Hz, 1H); 5.2 (d, J=17 Hz, 1H); 5.80 (m, 1H); 6.5 (d, J=8Hz, 1H); 6.8 (s, 1H); 6.8 (d, J=8 Hz, 1H); 7.05 (t, J=8 Hz, 1H); 7.1 (d,J=8 Hz, 1H); 7.4 (s, 1H); 7.45 (d, J=8 Hz, 1H); 9.3 (s, 1H).

EXAMPLE 25

3-((αS orαR)-α-(2R,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamidethe enantiomer of Example 23, was obtained after deprotection of thesecond isomer to elute from the column of Example 24. NMR (DMSO-d₆, 300MHz): δ 0.8 (d, J=5.5 Hz, 3H); 0.93 (d, J=6.3 Hz, 3H); 0.95-1.20 (m,6H); 2.12 (t, J=10.5 Hz, 1H); 2.20-2.40 (m, 3H); 2.54 (d, J=10.2 Hz,1H); 2.66-2.87 (m, 2H); 2.95-3.50 (m, 5H); 4.48 (s, 1H); 5.09 (d, J=11.5Hz, 1H); 5.14 (d, J=19.9 Hz, 1H); 5.80 (m, 1H); 6.52 (dd, J₁ =1.8 Hz, J₂7.6 Hz, 1H); 6.85 (d, J=8.1 Hz, 1H); 6.86 (s, 1H); 7.02 (t, J=7.6 Hz,1H); 7.10 (d, J=7.6 Hz, 1H); 7.31 (t, J=7.6 Hz, 1H); 7.34 (s, 1H); 7.45(d, J=7.9 Hz, 1H); 9.28 (s, 1H).

EXAMPLE 26(+)-3-((αS)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-phenylbenzamide

3-((αS)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-bromo-benzyl)phenol(2.30 g, 5.5 mmol, Example 9, infra) was treated withtert-butylchlorodimethylsilane (1.67 g, 11 mmol) and imidazole (0.94 g,13.8 mmol) in 30 mL of dimethylformamide at room temperature undernitrogen overnight. The reaction mixture was poured into ice-water andextracted with diethyl ether. The ethereal layers were washed with waterand brine, dried over sodium sulfate, and concentrated to dryness. Theresidue was purified by chromatography on silica gel with hexane:ethylacetate (0-50%) to give 2.36 g of the silyl ether as a yellow oil.

The silyl ether (2.25 g, 4.2 mmol) was dissolved in 80 mL of drytetrahydrofuran, dried further over molecular sieves, then transferredto a reaction flask under nitrogen and cooled to -78° C. n-Butyllithium(2.6 mL of a 1.6M solution in hexane) was added, while stirring undernitrogen, at a rate to keep the temperature below -70° C. Stirring wascontinued at -78° C. for 1 hour. Carbon dioxide was bubbled through thereaction mixture for 2-3 minutes. The mixture was warmed to roomtemperature with continual stirring to maintain steady degassing ofdissolved carbon dioxide. The solvent was evaporated, the residue wasredissolved in toluene, and the solvent was again removed under vacuumto eliminate all n-bromobutane. The residue was dissolved indichloromethane (50 mL), thionyl chloride (0.46 mL, 6.3 mmol) was added,and the mixture was stirred at room temperature for 40 minutes.Triethylamine (2.3 mL, 16.8 mmol) and N-methylaniline (0.5 mL, 4.6 mmol)were added, and stirring was continued at room temperature overnight.The reaction mixture was washed with water, dried over sodium sulfate,and the solvent was removed under vacuum to give 2.68 g of a brown oil.The crude product was dissolved in acetonitrile and treated with 1.2 g(6.3 mmol) of tetraethylammonium fluoride dihydrate at room temperaturefor 10 minutes. The solvent was evaporated and the residue was purifiedby chromatography on silica gel with dichloromethane:ethanol (0-3.5%) togive 0.92 g of(+)-3-((αS)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-phenylbenzamideas a light beige solid. NMR (DMSO-d₆, 200 MHz) δ 0.9 (d, J=6 Hz, 3H);0.95 (d, J=6 Hz, 3H); 1.7 (dd, J₁ =6 Hz, J₂ =8 Hz, 1H); 2.0 (dd, J₁ =7Hz, J₂ =10 Hz, 1H); 2.1 (m, 1H); 2.4-2.7 (m, 3H); 2.85 (dd, J₁ =7 Hz, J₂14 Hz, 1H); 3.15 (dd, J₁ =7 Hz, J₂ =15 Hz, 1H); 3.4 (s, 3H); 4.7 (s,1H); 5.1 (d, J=10 Hz, 1H); 5.2 (d, J=17 Hz, 1H); 5.8 (m, 1H); 6.6 (m,2H); 6.8 (s, 1H); 7.0 (t, J=8 Hz, 1H); 7.1-7.3 (m, 9H); 9.4 (s, 1H).α!_(D) ²⁰ =+4° (abs ethanol, c=2.7). The product was dissolved inabsolute ethanol and titrated to pH 3 with ethanolic hydrogen chloride.The solution was concentrated and diethyl ether was added to precipitatethe monohydrochloride salt which was dried under vacuum to give 0.617 gof a light beige powder. Calc. for C₃₀ H₃₅ N₃ O₂ HCl 0.70 H₂ O: C,69.47; H, 7.27; N, 8.10; Cl, 6.84. Found: C, 69.76; H, 7.27; N, 7.74;Cl, 6.60.

EXAMPLE 27(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-phenyl-N-propylbenzamide

N-Propylaniline was prepared from aniline and propionic anhydride,coupled with3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoylchloride, deprotected and purified by the methods described in Example10 to give(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-phenyl-N-propylbenzamideas a light yellow solid. NMR (200 MHz, DMSO-d₆): δ 0.87 (t, J=7.4 Hz,3H); 0.91 (d, J=5.9 Hz, 3H); 0.98 (d, J=6.0 Hz, 3H); 1.51 (m, 2H); 1.69(dd, J₁ =7.2 Hz, J₂ =10.9 Hz, 1H); 2.06 (dd, J₁ =7.0 Hz, J₂ =10.5 Hz,1H); 2.30 (d, J=10.3 Hz, 1H); 2.39-2.54 (m, 2H); 2.65 (br d, J=10.3 Hz,1H); 2.85 (dd, J₁ =7.4 Hz, J₂ =14.5 Hz, 1H); 3.16 (dd, J₁ =5.1 Hz, J₂=14.2 Hz, 1H); 3.79 (t, J=7.6 Hz, 2H); 4.77 (s, 1H); 5.12 (d, J=10.2 Hz,1H); 5.18 (d, J=16.0 Hz, 1H); 5.71-5.84 (m, 1H); 6.43 (d, J=7.6 Hz, 1H);6.57 (s, 1H); 6.64 (d, J=8.0 Hz, 1H); 7.02-7.33 (m, 10H); 9.32 (s, 1H).Mass spectrum (CI--CH₄) m/e: 498 (M+1, 100%), 344 (23%), 153 (80%).α!_(D) ²⁰ =+8.9° (ethanol, c=1.1). The free amine (0.585 g) wasdissolved in ethanol and titrated with ethanolic hydrogen chloride to pH4.0 followed by precipitation with diethyl ether from dichloromethane togive 0.479 g of the monohydrochloride salt as a hygroscopic off-whitepowder. Calc. for C₃₂ H₃₉ N₃ O₂ HCl 0.75 H₂ O: C, 70.18; H, 7.64; N,7.67; Cl, 6.47. Found: C, 70.16; H, 7.73; N, 7.59; Cl, 6.51.

EXAMPLE 28(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-(4-fluorophenyl)benzamide

Method A

4-Fluoro-N-ethylaniline NMR (200 MHz, DMSO-d₆): δ 1.25 (t, J=7.1 Hz,3H); 3.12 (q, J=7.1 Hz, 2H); 3.24 (br s, 1H); 6.57 (dd, J₁ =4.5 Hz, J₂=9.0 Hz, 2H); 6.90 (t, J=8.9 Hz, 2H)! was prepared from 4-fluoroanilineand acetic anhydride, coupled with 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoylchloride, deprotected and purified by the methods described in Example10 to give(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-(4-fluorophenyl)benzamideas an off-white powder. NMR (200 MHz, DMSO-d₆): δ 0.91 (d, J=6.1 Hz,3H); 0.98 (d, J=6.0 Hz, 3H); 1.08 (t, J=7.0 Hz, 3H); 1.71 (dd, J₁ =7.0Hz, J₂ =11.3 Hz, 1H); 2.05 (dd, J₁ =7.2 Hz, J₂ =10.8 Hz, 1H); 2.31 (d,J=11.4 Hz, 1H) 2.36-2.57 (m, 2H); 2.69 (dd, J₁ =2.2 Hz, J₂ =10.7 Hz,1H); 2.85 (dd, J₁ =7.0 Hz, J₂ =13.9 Hz, 1H); 3.18 (dd, J₁ =5.3 Hz, J₂=13.9 Hz, 1H); 3.84 (q, J=7.0 Hz, 2H); 4.78 (s, 1H); 5.11 (d, J=10.0 Hz,1H); 5.18 (d, J=16.4 Hz, 1H); 5.65-5.88 (m, 1H); 6.46 (d, J=7.4 Hz, 1H);6.58 (s, 1H); 6.65 (d, J=8.1 Hz, 1H); 7.01-7.27 (m, 9H); 9.33 (s, 1H).Mass spectrum (CI--CH₄) m/e: 502 (M+1, 90%), 348 (15%), 153 (100%).α!_(D) ²⁰ =+6.30° (abs. ethanol, c=1.1) The free amine (0.313 g) wasdissolved in ethanol and titrated with ethanolic hydrogen chloride to pH3.95 followed by precipitation with diethyl ether from dichloromethaneto give 0.263 g of the monohydrochloride salt as a hygroscopic whitepowder. Calc. for C₃₁ H₃₆ N₃ O₂ F HCl H₂ O: C, 66.95; H, 7.07; N, 7.56;Cl, 6.38. Found: C, 66.97; H, 7.10; N, 7.47; Cl, 6.41.

Method B

4-Fluoro-N-ethylaniline NMR (200 MHz, DMSO-d₆): δ 1.25 (t, J=7.1 Hz,3H); 3.12 (q, J=7.1 Hz, 2H); 3.24 (br s, 1H); 6.57 (dd, J₁ =4.5 Hz, J₂=9.0 Hz, 2H); 6.90 (t, J=8.9 Hz, 2H)! was prepared from 4-fluoroanilineand acetic anhydride by the methods described in Example 10. The anilinewas used to form N-(4-fluorophenyl)-3-formyl-N-ethylbenzamide NMR (200MHz, DMSO-d₆): δ 1.11 (t, J=7.0 Hz, 3H); 3.88 (q, J=7.0 Hz, 2H); 7.10(t, J=8.6 Hz, 2H); 7.21-7.35 (m, 2H); 7.46 (q, J=7.4 Hz, 1H); 7.56 (d,J=7.2 Hz, 1H); 7.83 (m, 2H); 9.93 (s, 1H)! by the methods described inExample 16, Method B.(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-(4-fluorophenyl)benzamidewas obtained as a white crystalline solid fromN-(4-fluorophenyl)-3-formyl-N-ethylbenzamide via crude3-(((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(1H-benzotriazol-1-yl)methyl)-N-ethyl-N-(4-fluorophenyl)benzamideusing the procedures described in Example 16, Method B. The finalrecrystallization was performed in acetonitrile to give colorlesscrystals, mp. 111-112° C. NMR (200 MHz, DMSO-d₆): δ 0.91 (d, J=6.1 Hz,3H); 0.98 (d, J=6.0 Hz, 3H); 1.08 (t, J=7.0 Hz, 3H); 1.71 (dd, J₁ =7.0Hz, J₂ =11.3 Hz, 1H); 2.05 (dd, J₁ =7.2 Hz, J₂ =10.8 Hz, 1H); 2.31 (d,J=11.4 Hz, 1H) 2.36-2.57 (m, 2H); 2.69 (dd, J₁ =2.2 Hz, J₂ =10.7 Hz,1H); 2.85 (dd, J₁ =7.0 Hz, J₂ =13.9 Hz, 1H); 3.18 (dd, J₁ =5.3 Hz, J₂=13.9 Hz, 1H); 3.84 (q, J=7.0 Hz, 2H); 4.78 (s, 1H); 5.11 (d, J=10.0 Hz,1H); 5.18 (d, J=16.4 Hz, 1H); 5.65-5.88 (m, 1H); 6.46 (d, J=7.4 Hz, 1H);6.58 (s, 1H); 6.65 (d, J=8.1 Hz, 1H); 7.01-7.27 (m, 9H); 9.33 (s, 1H).Mass spectrum (CI--CH₄) m/e: 502 (M+1, 90%), 348 (15%), 153 (100%).α!_(D) ²⁰ =+6.15° (abs. ethanol, c=1.0). The monohydrochloride salt maybe prepared as in Method A.

EXAMPLE 29(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-phenethylbenzamide

N-Methylphenethylamine was coupled with3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoylchloride, deprotected and purified by the methods described in Example10 to give(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-phenethylbenzamideas a light yellow powder. NMR (300 MHz, DMSO-d₆, 80° C.): δ 0.91 (d,J=5.5 Hz, 3H); 1.08 (d, J=6.3 Hz, 3H); 1.87 (dd, J₁ =7.1 Hz, J₂ =11.2Hz, 1H); 2.09 (dd, J₁ =7.1 Hz, J₂ =11.0 Hz, 1H); 2.58 (d, J=11.3 Hz,1H); 2.67 (m, 1H); 2.76 (dd, J₁ =6.2 Hz, J₂ =13.2 Hz, 1H); 2.77-2.87 (m,4H); 2.89 (s, 3H); 3.18 (dd, J₁ =5.5 Hz, J₂ =14.2 Hz, 1H); 3.55 (br s,2H); 4.97 (s, 1H); 5.10 (d, J=10.2 Hz, 1H); 5.16 (d, J=17.3 Hz, 1H);5.74-5.89 (m, 1H); 6.65-6.73 (m, 3H); 7.07-7.41 (m, 9H); 7.43 (d, J=7.9Hz, 1H); 9.07 (s, 1H). Mass spectrum (CI--CH₄) m/e: 498 (M+1, 88%), 344(22%), 153 (100%). α!_(D) ²⁰ =+3.8°0 (ethanol, c=1.25). The free amine(0.232 g) was dissolved in ethanol and titrated with ethanolic hydrogenchloride to pH 3.9 followed by precipitation with diethyl ether fromdichloromethane to give 0.205 g of the monohydrochloride salt as ahygroscopic light yellow powder. Calc. for C₃₂ H₃₉ N₃ O₂ HCl H₂ O: C,69.61; H, 7.67; N, 7.61; Cl, 6.42. Found: C, 69.51; H, 7.73; N, 7.47;Cl, 6.52.

EXAMPLE 30(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-methoxyphenyl)-N-methylbenzamide

4-Methoxy-N-methylaniline was coupled with3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoylchloride, deprotected and purified by the methods described in Example10 to give3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-methoxyphenyl)-N-methylbenzamideas a light purple powder. NMR (200 MHz, DMSO-d₆): δ 0.89 (d, J=6.0 Hz,3H); 0.96 (d, J=6.1 Hz, 3H); 1.66 (dd, J₁ =6.5 Hz, J₂ =11.0 Hz, 1H);2.00 (dd, J₁ =7.1 Hz, J₂ =10.4 Hz, 1H); 2.27 (br d, J=11.4 Hz, 1H);2.36-2.54 (m, 2H); 2.64 (d, J=11.6 Hz, 1H); 2.82 (dd, J₁ =6.9 Hz, J₂=13.6 Hz, 1H); 3.18 (dd, J₁ =5.4 Hz, J₂ =12.8 Hz, 1H); 3.30 (s, 3H);3.68 (s, 3H); 4.76 (s, 1H); 5.11 (d, J=10.6 Hz, 1H); 5.18 (d, J=17.1 Hz,1H); 5.66-5.88 (m, 1H); 6.42 (d, J=7.1 Hz, 1H); 6.58 (s, 1H); 6.63 (d,J=7.4 Hz, 1H); 6.78 (d, J=8.8 Hz, 2H); 6.97-7.24 (m, 7H); 9.34 (s, 1H).Mass spectrum (CI--CH₄) m/e: 500 (M+1, 79%), 346 (49%), 153 (100%).α!_(D) ²⁰ =+9.6° (abs. ethanol, c=1.0). The free amine was dissolved inethanol and titrated with ethanolic hydrogen chloride to pH 4.0 followedby precipitation with diethyl ether from dichloromethane to give themonohydrochloride salt as a hygroscopic light purple powder. Calc. forC₃₁ H₃₇ N₃ O₃ HCl H₂ O: C, 67.19; H, 7.28; N, 7.58; Cl, 6.40. Found: C,67.01; H, 7.30; N, 7.53; Cl, 6.42.

EXAMPLE 31(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(2-fluorophenyl)-N-methylbenzamide

2-Fluoro-N-methylaniline NMR (200 MHz, DMSO-d₆): δ 2.89 (s, 3H); 3.87(br s, 1H); 6.59-6.78 (m, 2H); 6.91-7.10 (m, 2H)! was prepared from2-fluoroaniline, coupled with3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoylchloride, deprotected and purified by the methods described in Example10 to give3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(2-fluorophenyl)-N-methylbenzamideas an off-white powder. NMR (200 MHz, DMSO-d₆): δ 0.92 (d, J=6.1 Hz,3H); 0.99 (d, J=6.1 Hz, 3H); 1.69 (dd, J₁ =6.7 Hz, J₂ =10.8 Hz, 1H);2.05 (dd, J₁ =7.6 Hz, J₂ =11.1 Hz, 1H); 2.30 (br d, J11.5 Hz, 1H);2.41-2.52 (m, 2H); 2.68 (br d, J=10.4 Hz, 1H); 2.83 (dd, J₁ =7.2 Hz, J₂=13.8 Hz, 1H); 3.20 (dd, J₁ =6.1 Hz, J₂ =14.2 Hz, 1H); 3.30 (s, 3H);4.82 (s, 1H); 5.12 (d, J=9.7 Hz, 5.18 (d, J=15.8 Hz, 1H); 5.72-5.86 (m,1H); 6.45 (d, J=7.4 Hz, 1H); 6.56 (s, 1H); 6.66 (d, J=8.0 Hz, 1H);7.05-7.38 (m, 9H); 9.33 (s, 1H). Mass spectrum (CI--CH₄) m/e: 488 (M+1,100%), 334 (45%), 153 (86%). α!_(D) ²⁰ =+2.02° (abs. ethanol, c=1.1).The free amine was dissolved in ethanol and titrated with ethanolichydrogen chloride to pH 4.0 followed by precipitation with diethyl etherfrom dichloromethane to give the monohydrochloride salt as a hygroscopicbeige powder. Calc. for C₃₀ H₃₄ N₃ O₂ F HCl 0.75 H₂ O: C, 67.03; H,6.84; N, 7.82; Cl, 6.59. Found: C, 67.05; H, 6.86; N, 7.77; Cl, 6.67.

EXAMPLE 32(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-allyl-N-phenylbenzamide

N-Allylaniline NMR (200 MHz, DMSO-d₆): δ 3.68 (t, J=5.2 Hz, 2H); 5.10(d, J=10.2 Hz, 1H); 5.23 (d, J=17.2 Hz, 1H); 5.78 (br s, 1H); 5.75-5.97(m, 1H); 6.52 (t, J=7.3 Hz, 2H); 6.56 (d, J=7.8 Hz, 2H); 7.06 (t, J=7.3Hz, 2H)! was prepared from aniline and allyl bromide viatrifluoroacetanilide using the general method described by Hodge(Harland, P. A.; Hodge, P; Maughan, W.; Wildsmith, E. Synthesis, 1984,941).

N-Allylaniline was coupled with3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoylchloride, deprotected and purified by the methods described in Example10 to give3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-allyl-N-phenylbenzamideas an off-white powder. NMR (200 MHz, DMSO-d₆): δ 0.91 (d, J=6.3 Hz,3H); 0.97 (d, J=5.8 Hz, 3H); 1.67 (dd, J₁ =6.7 Hz, J₂ =10.6 Hz, 1H);2.03 (dd, J₁ =7.0 Hz, J₂ =10.3 Hz, 1H); 2.29 (d, J=11.9 Hz, 1H);2.39-2.53 (m, 2H); 2.67 (br d, J=11.2 Hz, 1H); 2.83 (dd, J₁ =6.8 Hz, J₂=14.4 Hz, 1H); 3.17 (dr, J₁ =5.2 Hz, J₂ =14.0 Hz, 1H); 4.45 (d, J=5.5Hz, 2H); 4.78 (s, 1H); 5.11 (d, J=7.4 Hz, 1H); 5.12 (d, J=8.5 Hz, 1H);5.17 (d, J=11.9 Hz, 1H); 5.18 (d, J=15.3 Hz, 1H); 5.71-5.98 (m, 2H);6.42 (d, J=7.6 Hz, 1H); 6.56 (s, 1H); 6.65 (d, J=7.8 Hz, 1H); 7.02-7.33(m, 10H); 9.33 (s, 1H). Mass spectrum (CI--CH₄) m/e: 496 (M+1, 45%), 342(22%), 153 (100%). α!_(D) ²⁰ =+6.0° (abs. ethanol, c=1.1). The freeamine was dissolved in ethanol and titrated with ethanolic hydrogenchloride to pH 3.8 followed by precipitation with diethyl ether fromdichloromethane to give the monohydrochloride salt as a hygroscopicoff-white powder. Calc. for C₃₂ H₃₇ N₃ O₂ HCl H₂ O: C, 69.86; H, 7.33;N, 7.64; Cl, 6.44. Found: C, 69.94; H, 7.24; N, 7.62; Cl, 6.52.

EXAMPLE 33(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(cyclopropyl)methyl-N-phenylbenzamide

N-(Cyclopropylmethyl)aniline NMR (200 MHz, DMSO-d₆): δ 0.21 (m, 2H);0.51 (m, 2H); 1.01 (m, 1H); 3.63 (d, J=7.3 Hz, 1H); 3.80 (br s, 1H);5.78 (br s, 1H); 7.18 (t, J=7.2 Hz, 1H); 7.25 (d, J=7.8 Hz, 2H); 7.42(t, J=7.3 Hz, 2H)! was prepared from aniline and(bromomethyl)cyclopropane via trifluoroacetanilide using the generalmethod described by Hodge (Harland, P. A.; Hodge, P; Maughan, W.;Wildsmith, E. Synthesis, 1984, 941.).

N-(Cyclopropyl)methylaniline was coupled with3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoylchloride, deprotected and purified by the methods described in Example10 to give3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(cyclopropyl)methyl-N-phenylbenzamideas an off-white powder. NMR (200 MHz, DMSO-d₆): δ 0.09 (m, 2H); 0.39 (m,2H); 0.92 (d, J=6.3 Hz, 3H); 0.96 (d, J=6.2 Hz, 3H); 1.28 (m, 1H); 1.69(dd, J₁ =7.4 Hz, J₂ =11.5 Hz, 1H); 2.04 (dd, J₁ =6.6 Hz, J₂ =11.0 Hz,1H); 2.30 (br d, J=12.1 Hz, 1H); 2.40-2.54 (m, 2H); 2.67 (br d, J=9.8Hz, 1H); 2.85 (dd, J₁ =7.4 Hz, J₂ =13.7 Hz, 1H); 3.16 (dd, J₁ =4.5 Hz,J₂ =14.7 Hz, 1H); 3.72 (d, J=7.0 Hz, 2H); 4.77 (s, 1H); 5.12 (d, J=10.0Hz, 1H); 5.18 (d, J=15.6 Hz, 1H); 5.70-5.85 (m, 1H); 6.44 (d, J=7.3 Hz,1H); 6.57 (s, 1H); 6.65 (d, J=8.0 Hz, 1H); 7.02-7.33 (m, 10H); 9.33 (s,1H). Mass spectrum (CI--CH₄) m/e: 510 (M+1, 61%), 356 (42%), 153 (100%).α!_(D) ²⁰ =+8.9° (abs. ethanol, c=1.1). The free amine was dissolved inethanol and titrated with ethanolic hydrogen chloride to pH 3.75followed by precipitation with diethyl ether from dichloromethane togive the monohydrochloride salt as a hygroscopic off-white powder. Calc.for C₃₃ H₃₉ N₃ O₂ HCl 1.25 H₂ O: C, 69.70; H, 7.53; N, 7.39; Cl, 6.23.Found: C, 69.82; H, 7.52; N, 7.36; Cl, 6.28.

EXAMPLE 343-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-isopropyl-N-phenylbenzamide

N-Isopropylaniline NMR (200 MHz, DMSO-d₆): δ 1.13 (d, J=6.3 Hz, 6H);3.58 (m, 1H); 5.30 (d, J=8.0 Hz, 1H); 6.49 (t, J=7.2 Hz, 1H); 6.55 (d,J=7.8 Hz, 2H); 7.06 (t, J=7.6 Hz, 2H)! was prepared from aniline andacetone via reductive amination using the general method described bySchellenberg (Schellenberg, K. A. J. Org. Chem. 1963, 28, 3259).

N-Isopropylaniline was then coupled with3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)-benzyl)benzoylchloride, deprotected and purified by the methods described in Example10 to give3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-isopropyl-N-phenylbenzamideas an off-white solid. NMR (200 MHz, DMSO-d₆): δ 0.92 (d, J=6.1 Hz, 3H);0.99 (d, J=5.9 Hz, 3H); 1.11 (d, J=6.9 Hz, 6H); 1.70 (dd, J₁ =7.2 Hz, J₂=11.1 Hz, 1H); 2.07 (dd, J₁ =7.6 Hz, J₂ =10.6 Hz, 1H); 2.33 (br d, J=9.9Hz, 1H); 2.42-2.54 (m, 2H); 2.68 (br d, J=10.4 Hz, 1H); 2.85 (dd, J₁=6.5 Hz, J₂ =13.9 Hz, 1H); 3.16 (dd, J₁ =4.9 Hz, J₂ =14.1 Hz, 1H); 4.75(s, 1H); 4.85 (m, 1H); 5.10 (d, J=10.2 Hz, 1H); 5.18 (d, J=16.8 Hz, 1H);5.70-5.84 (m, 1H); 6.50 (d, J=7.1 Hz, 1H); 6.59 (s, 1H); 6.65 (d, J=8.2Hz, 1H); 7.03-7.32 (m, 10H); 9.33 (s, 1H). Mass spectrum (CI--CH₄) m/e:498 (M+1, 100%), 344 (43%), 153 (76%). α!_(D) ²⁰ =+6.4° (abs. ethanol,c=1.4). The free amine was dissolved in ethanol and titrated withethanolic hydrogen chloride to pH 4.0 followed by precipitation withdiethyl ether from dichloromethane to give the monohydrochloride salt asa hygroscopic off-white powder. Calc. for C₃₂ H₃₉ N₃ O₂ HCl 0.5 H₂ O: C,70.76; H, 7.61; N, 7.74; Cl, 6.53. Found: C, 71.01; H, 7.83; N, 7.49;Cl, 6.41.

EXAMPLE 353-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-cyclopropyl-N-phenylbenzamide

N-Cyclopropylaniline was prepared via the Barton approach for arylationof amines (Barton, D. H.; Finer, J-P.; Khamsi, J. Tetrahedron Lett.1987, 28, 887). Cyclopropylamine (1.0 g, 17.5 mmol.) was added totriphenylbismuth (9.25 g, 21.0 mmol.) and cupric acetate (1.6 g, 8.75mmol) in dichloromethane (30 mL) at room temperature under nitrogen. Themixture was stirred for 18 hours, filtered over a short plug of celiteto remove any insoluble material, and purified by chromatography on asilica gel column (4 cm×10 cm) using hexane/ethyl acetate (95/5) forelution. The fraction containing the desired product was stripped of allvolatiles under vacuum to yield N-cyclopropylaniline (0.8 g). NMR (200MHz, DMSO-d₆): δ 0.37 (m, 2H); 0.68 (m, 2H); 2.30 (m, 1H); 6.03 (br s,1H); 6.56 (t, J=7.4 Hz, 1H); 6.70 (d, J=8.2 Hz, 2H); 7.09 (t, J=7.8 Hz,2H)

N-Cyclopropylaniline was then be coupled with3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)-benzyl)benzoylchloride, deprotected and purified by the methods described in Example10 to give3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-cyclopropyl-N-phenylbenzamideas a yellow powder. NMR (200 MHz, DMSO-d₆): δ 0.44 (m, 2H); 0.70 (m,2H); 0.93 (d, J=6.1 Hz, 3H); 1.01 (d, J=5.7 Hz, 3H); 1.74 (dd, J₁ =7.7Hz, J₂ =11.8 Hz, 1H); 2.05 (dd, J₁ =6.8 Hz, J₂ =11.1 Hz, 1H); 2.39 (brd, J=10.5 Hz, 1H); 2.41-2.54 (m, 2H); 2.69 (br d, J=11.8 Hz, 1H); 2.83(dd, J₁ =6.6 Hz, J₂ =13.6 Hz, 1H); 3.05-3.36 (m, 2H); 4.83 (s, 1H); 5.10(d, J=9.8 Hz, 1H); 5.17 (d, J=17.4 Hz, 1H); 5.70-5.86 (m, 1H); 6.57 (d,J=7.1 Hz, 1H); 6.63 (s, 1H); 6.65 (d, J=8.2 Hz, 1H); 7.03-7.38 (m, 10H);9.34 (s, 1H). Mass spectrum (CI--CH₄) m/e: 496 (M+1, 100%), 342 (45%),153 (90%). α!_(D) ²⁰ =+7.1° (abs. ethanol, c=1.1). The free amine wasdissolved in ethanol and titrated with ethanolic hydrogen chloride to pH3.95 followed by precipitation with diethyl ether from dichloromethaneto give the monohydrochloride salt as a hygroscopic orange powder. Calc.for C₃₂ H₃₇ N₃ O₂ HCl 1.50H₂ O: C, 68.74; H, 7.39; N, 7.51; Cl, 6.34.Found: C, 68.56; H, 7.49; N, 7.26; Cl, 6.37.

EXAMPLE 36(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-(3-fluorophenyl)benzamide

3-Fluoro-N-ethylaniline NMR (DMSO-d₆, 200 MHz): δ 1.18 (t, J=7.2 Hz,3H); 3.02 (dq, J₁ =7.2 Hz, J₂ =7.2 Hz, 2H); 5.86 (br m, 1H); 6.24-6.42(m, 3H); 7.07 (q, J=7.8 Hz, 1H)! was prepared from 3-fluoroaniline andacetic anhydride, coupled with3-((α)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoylchloride, deprotected and purified by the methods described in Example10 to give(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-(3-fluorophenyl)benzamideas a white solid. NMR (DMSO-d₆, 200 MHz): δ 0.92 (d, J=6 Hz, 3H); 0.96(d, J=6 Hz, 3H); 1.05 (t, J=7 Hz, 3H); 1.7 (m, 1H); 2.05 (m, 1H); 2.3(m, 1H); 2.5 (m, 2H); 2.7 (m, 1H); 2.9 (m, 1H); 3.2 (m, 1H); 3.9 (q, J=7Hz, 2 H); 4.8 (s, 1H); 5.1 (d, J=10 Hz, 1H); 5.2 (d, J=16 Hz, 1H); 5.8(m, 1H); 6.45 (d, J=8 Hz, 1H); 6.6 (s, 1H); 6.65 (d, J=8 Hz, 1H); 6.9(d, J=8 Hz, 1H); 7.0-7.2 (m, 3H); 7.2-7.4 (m, 5H); 9.35 (s, 1H). α!_(D)²⁰ =+4.3° (abs EtOH, c=3.9). Calc. for C₃₁ H₃₆ FN₃ O₂ HCl 0.5 H₂ O: C,68.06; H, 7.00; N, 7.68; Cl, 6.48. Found: C, 68.10; H, 7.04; N, 7.63;Cl, 6.42. Mass spectrum (CI--CH₄) m/e: 502 (M+1, 39%), 501 (M, 9%), 348(29%), 153 (100%).

EXAMPLE 37(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(2-fluorophenyl)-N-propylbenzamide

2-Fluoro-N-propylaniline NMR (DMSO-d₆, 200 MHz): δ 0.93 (t, J=7.4 Hz,3H); 1.59 (m, 2H); 3.04 (q, 6.5 Hz, 2H); 5.33 (br m, 1H); 6.47-6.58 (m,1H); 6.70 (t, J=8.1 Hz, 1H); 6.93-7.05 (m, 2H)! was prepared from2-fluoroaniline and propionic anhydride, coupled with3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoylchloride, deprotected and purified by the methods described in Example10 to give(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(2-fluorophenyl)-N-propylbenzamideas a white solid. NMR (DMSO-d₆, 200 MHz): δ 0.9-1.05 (m, 9H); 1.5 (m,2H); 1.7 (m, 1H); 2.05 (m, 1H); 2.3 (m, 1H); 2.5 (m, 2H); 2.7 (m, 1H);2.85 (m, 1H); 3.2 (m, 1H); 3.7 (m, 2 H); 4.8 (br s, 1H); 5.1 (d, J=10Hz, 1H); 5.2 (d, J=16 Hz, 1H); 5.8 (m, 1H); 6.5 (d, J=8 Hz, 1H); 6.6 (s,1H); 6.65 (d, J=8 Hz, 1H); 7.0-7.4 (m, 9H); 9.3 (s, 1H). α!_(D) ²⁰=+1.8° (abs ethanol, c=2.8). Calc. for C₃₂ H₃₈ FN₃ O₂ HCl 0.25 H₂ O: C,69.05; H, 7.15; N, 7.55; Cl, 6.37. Found: C, 68.94; H, 7.19; N, 7.57;Cl, 6.41. Mass spectrum (CI--CH₄) m/e: 516 (M+1, 93%), 515 (M, 29%), 362(26%), 153 (100%).

EXAMPLE 38(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-(2-fluorophenyl)benzamide

2-Fluoro-N-ethylaniline NMR (DMSO-d₆, 200 MHz): δ 1.16 (t, J=7.1 Hz,3H); 3.11 (dq, J₁ =7.2 Hz, J₂ =6.5 Hz, 2H); 5.30 (br m, 1H); 6.48-6.59(m, 1H); 6.70 (t, J=8.5 Hz, 1H); 6.92-7.06 (m, 2H)! was prepared from2-fluoroaniline and acetic anhydride, coupled with3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoylchloride, deprotected and purified by the methods described in Example10 to give(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-(2-fluorophenyl)benzamideas a light yellow wax. NMR (DMSO-d₆, 200 MHz): δ 0.9 (d, J=6 Hz, 3H);0.95 (d, J=6 Hz, 3H); 1.1 (t, J=7 Hz, 1H); 2.1 (m, 1H); 2.3 (m, 1H); 2.5(m, 2H); 2.7 (m, 1H); 2.85 (m, 1H); 3.8 (br m, 2H); 4.8 (br s, 1H); 5.1(d, J=10 Hz, 1H); 5.2 (d, J=17 Hz, 1H); 5.8 (m, 1H); 6.45 (m, 1H); 6.5(s, 1H); 6.65 (m, 1H); 7.0-7.4 (m, 9H); 9.35 (s, 1H). α!_(D) ²⁰ =+3.4°(abs ethanol, c=2.04). Calc. for C₃₁ H₃₆ FN₃ O₂ HCl H₂ O: C, 66.95; H,7.07; N, 7.56; Cl, 6.38. Found: C, 66.61; H, 7.14; N, 7.53; Cl, 6.40.Mass spectrum (CI--CH₄) m/e: 502 (M+1, 89%), 501 (M, 17%), 348 (36%),153 (100%).

EXAMPLE 39(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-propylbenzamide

3-Fluoro-N-propylaniline NMR (DMSO-d₆, 200 MHz): δ 0.96 (t, J=7.3 Hz,3H); 1.56 (m, 2H); 2.97 (q, 6.9 Hz, 2H); 5.93 (br m, 1H); 6.22-6.43 (m,3H); 7.06 (q, J=7.8 Hz, 1H)! was prepared from 3-fluoroaniline andpropionic anhydride, coupled with3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoylchloride, deprotected and purified by the methods described in Example10 to give(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-propylbenzamideas a light beige solid. NMR (DMSO-d₆, 200 MHz): α0.9-1.05 (m, 9H); 1.5(m, 2H); 1.7 (m, 1H); 2.05 (m, 1H); 2.3 (m, 1H); 2.5 (m, 2H); 2.7 (m,1H); 2.85 (m, 1H); 3.8 (m, 2H); 4.8 (s, 1H); 5.1 (d, J=10 Hz, 1H); 5.2(d, J=16 Hz, 1H); 5.8 (m, 1H); 6.45 (d, J=8 Hz, 1H); 6.6 (s, 1H); 6.7(d, J=8 Hz, 1H); 6.9 (d, J=8 Hz, 1H); 7.0-7.4 (m, 9H); 9.3 (s, 1H).α!_(D) ²⁰ =+4.3° (abs ethanol, c=1.5). Calc. for C₃₂ H₃₈ FN₃ O₂ HCl 0.75H₂ O: C, 67.95; H, 7.22; N, 7.43; Cl, 6.27. Found: C, 67.72; H, 7.19; N,7.49; Cl, 6.30. Mass spectrum (CI--CH₄) m/e: 516 (M+1, 100%), 515 (M,22%), 362 (30%), 153 (73%).

EXAMPLES 40-41

The following compounds may be made by forming the appropriatelysubstituted aniline (which is available from the parent aniline andappropriate carboxylic acid anhydride as described in Example 10),coupling with3-((α)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoylchloride, deprotecting and purifying by the methods described in Example10. The monohydrochloride salts may be formed using ethanolic hydrogenchloride as described in Example 10.

3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-methoxyphenyl)-N-propylbenzamide

3-((α)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-(4-methoxyphenyl)benzamide

EXAMPLE 423-((α)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-(N-(3-fluorophenyl)-N-methylcarbamoyl)benzyl)phenylmonophosphate

(+)-3-((α)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide(Example 16, 0.75 g, 1.54 mmol) was dissolved in dry pyridine (10 mL)under a nitrogen atmosphere. The solution was cooled to -10° C. in anice and methanol bath. Phosphoryl chloride (0.49 g) was added slowly tothe cold solution. The reaction was allowed to stir for 45 minutes,warming gradually, under a nitrogen atmosphere. Water (20 mL) was addedto the solution. The solution was stirred for 30 minutes at roomtemperature. Ammonium hydroxide (15M, 0.85 mL) was added and allvolatiles were removed under reduced pressure. The residue was slurriedin acetone and filtered. The filtrate was evaporated under reducedpressure to give a quantitative yield of crude product as a light yellowpowder. The crude product (0.56 g) was dissolved in 15 mL of water andpurified by ion exchange chromatography (12 g, AG 1-x8 Resin, 100-200mesh, formate form converted to bicarbonate form, Bio-Rad Laboratories,Hercules, Calif.), eluting with water. The desired material eluted inthe first fractions. The solvent was concentrated to a small volumeunder reduced pressure and lyophilized to give 0.39 g of3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(N-(3-fluorophenyl)-N-methylcarbamoyl)benzyl)phenylmonophosphate a fluffy white powder (dec. 154°-155° C.). NMR (200 MHz,DMSO-d₆): δ 1.08 (d, J=5.0 Hz, 3H); 1.17 (d, J=5.2 Hz, 3H); 2.04-2.61(m, 5H); 2.79-3.16 (m, 2H); 3.38 (s, 3H); 3.71 (m, 1H); 5.19 (s, 1H);5.38-5.57 (m, 2H); 5.82-6.03 (m, 1H); 6.39 (d, J=7.0 Hz, 1H); 6.82-7.39(m, 11H). Mass spectrum (Ion spray) m/e: 1135 (2M+1, 11%), 568 (M+1,100%), 414 (21%). α!_(D) ²⁰ =-9.1° (ethanol, c=1.0). Calc. for C₃₀ H₃₅FN₃ O₅ P 1.25 H₂ O 0.25 NH₃ : C, 60.62 H, 6.49; N, 7.66. Found: C,60.60; H, 6.42; N, 7.44.

EXAMPLE 43(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide

Crude3-(((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(1H-benzotriazol-1-yl)methyl)-N-(3-fluorophenyl)-N-methylbenzamidewas prepared from (2R,5S)-1-allyl-2,5-dimethylpiperazine (1.89 g),benzotriazole (1.39 g), andN-(3-fluorophenyl)-3-formyl-N-methylbenzamide (3.0 g) in toluene asdescribed in Example 16, Method B.

3-Bromoanisole (4.36 g) was dissolved in dry tetrahydrofuran (40 mL),and cooled to -78° C. under nitrogen. n-Butyllithium in hexanes (9.2 mLof a 2.5M solution) was added slowly via syringe to the solution. Whilestirring for 25 minutes at -78° C., the solution became white andsomewhat thick. The solution was transferred via a double-ended needleto a flask containing magnesium bromide etherate (6.02 g) intetrahydrofuran (60 mL) and stirred for 1 hour at room temperature. Thecrude3-(((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(1H-benzotriazol-1-yl)methyl)-N-(3-fluorophenyl)-N-methylbenzamidein toluene was added to the arylmagnesium bromide reagent just prepared.The solution warmed slightly during the addition and became a cloudyyellow-brown color. After stirring at room temperature for 2.5 hours,0.5M aqueous hydrochloric acid was added cautiously until the solutionreached pH=5. The product was extracted with 100 mL of ethyl acetate andthe solvent was removed under vacuum. The residue was taken up in 25 mLof 3N aqueous hydrochloric acid at room temperature. Diethyl ether wasadded, and the acidic aqueous layer was separated. The aqueous layer waswashed a second time with diethyl ether and adjusted to pH=10 usingaqueous sodium hydroxide solution. The product was extracted with ethylacetate. The ethyl acetate portions were combined, washed with dilutesodium hydroxide solution to remove any remaining benzotriazole, washedwith saturated sodium chloride solution, dried over sodium sulfate, andevaporated under reduced pressure. The crude product was purified bychromatography on a column of silica gel using 1% ethanol indichloromethane as the eluant to give 1.71 g of(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamideas a white crystalline solid in greater than 98% isomeric purity (asdetermined by HPLC, performed on a m-Bondapak C-18 column (125 Å,3.9×300 mm, Waters Chromatography Division, Millipore Corporation,Milford, Mass.) using 70% methanol and 30% 0.1M aqueous ammonium acetateat a flow rate of 1 mL/min.). NMR (200 MHz, DMSO-d₆): δ 0.91 (d, J=6.0Hz, 3H); 1.00 (d, J=6.2 Hz, 3H); 1.69 (dd, J₁ =7.1 Hz, J₂ =11.0 Hz, 1H);2.05 (dd, J₁ =7.5 Hz, J₂ =11.0 Hz, 1H); 2.31 (br d, J=9.3 Hz, 1H);2.42-2.53 (m, 2H); 2.69 (br d, J=11.2 Hz, 1H); 2.85 (dd, J₁ =7.0 Hz, J₂=14.1 Hz, 1H); 3.18 (dd, J₁ =5.5 Hz, J₂ =13.5 Hz, 1H); 3.37 (s, 3H);3.74 (s, 3H); 4.88 (s, 1H); 5.12 (d, J=10.0 Hz, 1H); 5.18 (d, J=15.7 Hz,1H); 5.70-5.83 (m, 1H); 6.58 (d, J=7.6 Hz, 1H); 6.70 (s, 1H); 6.84 (d,J=8.2 Hz, 1H); 6.94 (t, J=7.8 Hz, 1H); 7.02-7.14 (m, 2H); 7.18-7.34 (m,6H); 9.31 (s, 1H). Mass spectrum (CI--CH₄) m/e: 502 (m+1, 100%), 348(81%), 153 (12%). α!_(D) ²⁰ =+7.73° (abs. ethanol, c=1.1). The freeamine was dissolved in ethanol and titrated with ethanolic hydrogenchloride to pH 4.0 followed by precipitation with diethyl ether fromdichloromethane to give the monohydrochloride salt as a hygroscopiclight yellow powder. Calc. for C₃₁ H₃₆ N₃ O₂ F HCl 0.5 H₂ O: C, 68.06;H, 7.00; N, 7.68; Cl, 6.48. Found: C, 68.13; H, 7.12; N, 7.55; Cl, 6.35.

EXAMPLE 44(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N-ethyl-N-(4-fluorophenyl)benzamide

The compound was prepared from crude3-(((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(1H-benzotriazol-1-yl)methyl)-N-ethyl-N-(4-fluorophenyl)benzamide(Example 28, Method B, infra) and 3-bromoanisole by methods described inExample 16, Method B. NMR (200 MHz, DMSO-d₆): δ 0.91 (d, J=6.2 Hz, 3H);0.99 (d, J=6.3 Hz, 3H); 1.08 (t, J=7.0 Hz, 3H); 1.71 (dd, J₁ =7.0 Hz, J₂=11.1 Hz, 1H); 2.03 (dd, J₁ =7.1 Hz, J₂ =10.9 Hz, 1H); 2.31 (d, J=11.2Hz, 1H); 2.40-2.57 (m, 2H); 2.67 (d, J=11.5 Hz, 1H); 2.84 (dd, J₁ =6.6Hz, J₂ =13.9 Hz, 1H); 3.17 (dd, J₁ =5.5 Hz, J₂ =13.9 Hz, 1H); 3.74 (s,3H); 3.83 (q, J=7.0 Hz, 2H); 4.83 (s, 1H); 5.11 (d, J=10.2 Hz, 1H); 5.18(d, J=16.4 Hz, 1H); 5.63-5.85 (m, 1H); 6.60 (d, J=7.4 Hz, 1H); 6.71 (s,1H); 6.84 (d, J=8.2 Hz, 1H); 7.02-7.28 (m, 9H). Mass spectrum (CI--CH₄)m/e: 516 (M+1, 38%), 362 (100%), 153 (16%).

EXAMPLE 45

Selected compounds of the present invention, identified below withreference to the appertaining synthesis Examples hereof, were evaluatedfor in vitro opioid receptor activity in various receptor systems,including delta receptor agonism in the mouse vas deferens (Mouse VasDeferens ED₅₀), and mu receptor agonism in the guinea pig ileum (GuineaPig Ileum ED₅₀).

The assay procedures used for such determinations of receptor activityare set out below.

In vitro bioassays:

Vasa deferentia were removed from mice and suspended between platinumelectrodes with 0.5 g of tension in organ bath chambers containing amodified Krebs buffer of the following composition (millimolar): NaCl,118; KCl, 4.75; CaCl₂, 2.6; KH₂ PO₄, 1.20; NaHCO₃, 24.5; and glucose,11. The buffer was saturated with 95% O₂ /5% CO₂ and kept at 37° C.Tissues were stimulated at supramaximal voltage with 10 Hz pulse trainsfor 400 msec.; train interval 10 seconds; and 0.5 msec pulse duration.Intact ileums (about 3 cm length) were removed from guinea pig andsuspended with 1 g of tension in a bath chamber as described for thevasa deferentia. The modified Krebs' buffer also contained MgSO₄ (1.20mM). The ileums were stimulated with electrical square-wave pulses of0.1 Hz, 0.5 msec pulse duration at supramaximal voltage. The percentageinhibition of the electrically induced muscle contractions wasdetermined for the compounds at varying cumulative concentrations. TheED₅₀ values were extrapolated from curves showing the dose concentrationplotted against the response (J. A. H. Lord, A. A. Waterfield, J.Hughes, H. W. Kosterlitz, Nature 267, 495, (1977)).

Results are shown in Table A below.

                  TABLE A                                                         ______________________________________                                        In Vitro Opioid Receptor Activity.sup.a                                                   Delta-Receptor Mu-Receptor                                                    Mouse Vas      Guinea Pig                                         Example     Deferens ED.sub.50 (nM)                                                                      Ileum ED.sub.50 (nM)                               ______________________________________                                        1           7.3 (16)       18 (16)                                            9           0.48 (8)       1.23 (12)                                          10          0.35 (12)      0.67 (8)                                           12          0.93 (12)      1.08 (12)                                          16          0.47 (8)       3.3 (8)                                            28          0.39 (11)      4.0 (4)                                            31          0.39 (4)       4.4 (4)                                            ______________________________________                                         .sup.a Values are the mean of (n) number of experiments.                 

EXAMPLE 46

Analgesic activity was assessed by the tail pinch assay in rats (maleSprague-Dawley CD strain, weight approximately 300 g) after intravenous(i.v.) tail vein injection. A group of 6 to 8 animals was injected i.v.with compound in sterile 5% dextrose solution at a concentration of 1-5mg/mL. Five minutes after injection, an artery clamp (Fisher ScientificCo., self-closing artery forcep, catalog #08-905) was placed on the tailabout one inch from the tip of the tail to induce pressure nociceptionfor a short duration (maximum of 20 seconds). The nociceptive responsewas judged by any sign of discomfort, such as running, squeaking, orturning around to bite the clamp. The dose-response curve was plottedfor each compound. The analgesic potency (half-maximum effective dose,ED₅₀) was determined by the dose at which half of the animals do notshow any nociceptive response to the artery clamp pressure within 20seconds. Antinociceptive ED₅₀ doses were 0.35, 0.03, 0.04, and 0.03mg/kg for the compounds of Examples 1, 16, 27, and 28, respectively.

Pharmaceutical Formulations

In the following formulation Examples, the "Active Ingredient" may beany compound of the invention, such as a compound of formulae (I) and(II).

EXAMPLE 47

Tablet Formulations

The following formulations A, B and C are prepared by wet granulation ofthe ingredients with a solution of povidone, followed by addition of themagnesium stearate and compression.

Formulation A

    ______________________________________                                                           mg/tablet                                                                              mg/tablet                                         ______________________________________                                        (a) Active Ingredient                                                                            100      100                                               (b) Lactose B.P.   210      26                                                (c) Povidone B.P.  15       9                                                 (d) Sodium Starch Glycollate                                                                     20       12                                                (e) Magnesium Stearate                                                                           5        3                                                                    350      150                                               ______________________________________                                    

Formulation B

    ______________________________________                                                           mg/tablet                                                                              mg/tablet                                         ______________________________________                                        (a) Active Ingredient                                                                            100      100                                               (b) Lactose        150      --                                                (c) Avicel PH 101  60       26                                                (d) Povidone B.P.  15       9                                                 (e) Sodium Starch Glycollate                                                                     0        12                                                (f) Magnesium Stearate                                                                           5        3                                                                    350      150                                               ______________________________________                                    

Formulation C

    ______________________________________                                                         mg/tablet                                                    ______________________________________                                        Active Ingredient                                                                              100                                                          Lactose          200                                                          Starch           50                                                           Povidone         5                                                            Magnesium stearate                                                                             4                                                                             359                                                          ______________________________________                                    

The following formulations, D and E, are prepared by direct compressionof the admixed ingredients.

Formulation D

    ______________________________________                                                           mg/tablet                                                  ______________________________________                                        Active ingredient  100                                                        Pregelatinised Starch NF15                                                                       50                                                                            150                                                        ______________________________________                                    

Formulation E

    ______________________________________                                                        mg/tablet                                                     ______________________________________                                        Active ingredient                                                                             100                                                           Lactose         150                                                           Avicel          100                                                                           350                                                           ______________________________________                                    

Formulation F (Controlled Release Formulation)

The formulation is prepared by wet granulation of the followingingredients with a solution of povidone followed by addition of themagnesium stearate and compression.

    ______________________________________                                                             mg/tablet                                                ______________________________________                                        (a) Active Ingredient                                                                              500                                                      (b) Hydroxypropylmethylcellulose                                                                   112                                                      (Methocel K4M Premium)                                                        (c) Lactose B.P.     53                                                       (d) Povidone B.P.C.  28                                                       (e) Magnesium Stearate                                                                             7                                                                             500                                                      ______________________________________                                    

Drug release takes place over a period of about 6-8 hours and iscomplete after 12 hours.

EXAMPLE 48 Capsule Formulations

Formulation A

A capsule formulation is prepared by admixing the ingredients ofFormulation D in Example 62 above and filling into two-pan hard gelatincapsules.

Formulation B

    ______________________________________                                                           mg/capsule                                                 ______________________________________                                        (a) Active Ingredient                                                                            100                                                        (b) Lactose B.P.   143                                                        (c) Sodium Starch Glycollate                                                                     25                                                         (d) Magnesium Stearate                                                                           2                                                                             270                                                        ______________________________________                                    

Capsules are prepared by admixing the above ingredients and filling intotwo-part hard gelatin capsules.

Formulation C

    ______________________________________                                                         mg/capsule                                                   ______________________________________                                        (a) Active Ingredient                                                                          100                                                          (b) Macrogel 4000 BP                                                                           350                                                                           450                                                          ______________________________________                                    

Capsules are prepared by melting the Macrogel 4000 BP, dispersing theactive ingredient in the melt and filling the melt into two-pan hardgelatin capsules.

Formulation D

    ______________________________________                                                        mg/capsule                                                    ______________________________________                                        Active Ingredient                                                                             100                                                           Lecithin        100                                                           Arachis Oil     100                                                                           300                                                           ______________________________________                                    

Capsules are prepared by dispersing the active ingredient in thelecithin and arachis oil and filling the dispersion into soft, elasticgelatin capsules.

Formulation E (Controlled Release Capsule)

The following controlled release capsule formulation is prepared byextruding ingredients (a), (b) and (c) using an extruder, followed byspheronisation of the extrudate and drying. The dried pellets are thencoated with the release-controlling membrane (d) and filled intotwo-piece, hard gelatin capsules.

    ______________________________________                                                           mg/capsule                                                 ______________________________________                                        (a) Active Ingredient                                                                            250                                                        (b) Microcrystalline Cellulose                                                                   125                                                        (c) Lactose BP     125                                                        (d) Ethyl Cellulose                                                                              13                                                                            513                                                        ______________________________________                                    

EXAMPLE 49 Injectable Formulation

Formulation A

Active Ingredient 5.0 mg

Hydrochloric acid solution, 0.1M q.s. to pH 4.0 to 7.0

Sodium hydroxide solution, 0.1M q.s. to pH 4.0 to 7.0

Sterile Water q.s. to 10 ml

The active ingredient is dissolved in most of the water (35°-40° C.) andthe pH adjusted to between 4.0 and 7.0 using the hydrochloric acid orthe sodium hydroxide as appropriate. The batch is then made up to volumewith the water and filtered through a sterile micropore filter into asterile amber glass vial 10ml and sealed with sterile closures andoverseals.

Formulation B

Active Ingredient 12.5 mg

Sterile, pyrogen-free, pH 7 phosphate buffer q.s. to 25 ml

EXAMPLE 50 Intramuscular Injection

Active Ingredient 4.0 mg

Benzyl Alcohol 0.10 g

Glycofural 75 1.45 g

Water for Injection q.s. to 4.00 ml

The active ingredient is dissolved in the glycofural. The benzyl alcoholis then added and dissolved, and water added to 4 ml. The resultingmixture is filtered through a sterile micropore filter and sealed insterile amber glass vials.

EXAMPLE 51 Syrup

Active Ingredient 0.025 g

Sorbitol Solution 0.10 g

Glycerol 2.00 g

Sodium Benzoate 0.005 g

Flavour, Peach 17.42.3169 0.0125 ml

Purified Water q.s. to 5.00 ml

The active ingredient is dissolved in a mixture of the glycerol and mostof the purified water. An aqueous solution of the sodium benzoate isthen added to the solution, followed by addition of the sorbitolsolution and finally the flavour. The volume is made up with purifiedwater and mixed well.

EXAMPLE

    ______________________________________                                                            mg/suppository                                            ______________________________________                                        Active Ingredient   30                                                        Hard Fat, BP (Witepsol H15 -                                                                      1970                                                      Dynamit Nobel)                                                                                    2000                                                      ______________________________________                                    

One-fifth of the Witepsol H15 is melted in a steam-jacketed pan at 45°C. maxiumum. The active ingredient is sifted through a 200 mm sieve andadded to the molten base with mixing, using a Silverson fitted with acutting head, until a smooth dispersion is achieved. Maintaining themixture at 45° C., the remaining Witepsol H15 is added to the suspensionand stirred to ensure a homogeneous mix. The entire suspension is passedthrough a 250 mm stainless steel screen and, with continuous stirring,is allowed to cool to 40° C. At a temperature of 38° C. to 40° C., 2.0 gof the mixture is filled into suitable, 2 ml plastic molds. Thesuppositories are allowed to cool to room temperature.

EXAMPLE 53

Set out below is an illustrative formulation for pessaries comprising atleast one of the diarylmethyl piperazine compounds of the presentinvention.

Pessaries

    ______________________________________                                                         mg/pessary                                                   ______________________________________                                        Active Ingredient                                                                              30                                                           Anhydrate Dextrose                                                                             490                                                          Potato Starch    473                                                          Magnesium Stearate                                                                             7                                                                             1000                                                         ______________________________________                                    

The above ingredients are mixed directly and pessaries prepared bydirect compression of the resulting mixture.

EXAMPLE 54

Set out below are additional illustrative formulations in which thecompounds of the invention may be usefully employed, includingformulations in the dosage forms of oral suspensions, injectablesuspensions, nebulization suspensions, aerosol formulations, powderinhalation formulations, and nasal drops.

Tablet

    ______________________________________                                        Compound of formula (I) 25.0   mg                                             Lactose BP              48.5   mg                                             Microcrystalline Cellulose BP                                                                         10.0   mg                                             ("Avicel pH 101")                                                             Low-substituted Hydroxypropyl;                                                                        10     mg                                             Cellulose BP ("LHPC LH-11")                                                   Sodium Starch Glycollate BP                                                                           3      mg                                             ("Explotab")                                                                  Povidone BP ("K30")     3.0    mg                                             Magnesium Stearate BP   0.5    mg                                                                     100.0  mg                                             ______________________________________                                    

Oral Suspension

    ______________________________________                                        Compound of formula (I)                                                                             50      mg                                              Avicel RC 591         75      mg                                              Sucrose syrup         3.5     ml                                              Methylhydroxybenzoate 5       mg                                              Color                 0.01%   w/v                                             Cherry flavor         0.1%    v/v                                             Tween 80              0.2%    v/v                                             Water                 to 5    ml                                              ______________________________________                                    

Injectable Suspension

    ______________________________________                                        Compound of formula (I) 1.5 mg                                                Polyvinyl pyrrolidone (PVP)                                                                           170 mg                                                Tween 80                0.2% v/v                                              Methylhydroxybenzoate   0.1% w/v                                              Water for injection     to 3 ml                                               ______________________________________                                    

Capsule Formulation

    ______________________________________                                        Compound of formula (I) 1.5 mg                                                Starch 1500             150 mg                                                Magnesium stearate      2.5 mg                                                ______________________________________                                    

Fill the above-described formulation into a hard gelatin capsule.

Suspension for Nebulization

    ______________________________________                                        Compound of formula (I), sterile                                                                      1.0 mg                                                Water for injection     to 10.0 ml                                            ______________________________________                                    

Disperse the compound of formula (I) in the water for injection, aspreviously sterilized in a sterile container. Fill into sterile glassampoules, 10 ml/ampoule under sterile conditions, and seal each ampouleby fusion of the glass.

Aerosol Formulation

    ______________________________________                                        Compound of formula (I),                                                                             1.0 mg                                                 micronized                                                                    Aerosol propellant     to 5.0 ml                                              ______________________________________                                    

Suspend the micronized compound of formula (I) in the aerosolpropellant. Fill this suspension into preformed aerosol cannisters, 5ml/cannister under pressure, through the valve orifice.

Powder Inhalation

    ______________________________________                                        Compound of formula (I),                                                                              1.0 mg                                                micronized                                                                    Lactose                 29.0 mg                                               ______________________________________                                    

Triturate and blend the micronized compound of formula (I) with thelactose. Fill the resulting powder blend into hard gelatin capsuleshells, 30 mg per capsule.

Nasal Drops

    ______________________________________                                        Compound of formula (I)                                                                              20.0 mg                                                Methylhydroxybenzoate  10.0 mg                                                Water for Injection    to 10.0 ml                                             ______________________________________                                    

Disperse the compound of formula (I) and the methylhydroxybenzoate inthe water for injection. Fill this suspension into suitable dropperbottles, 10 ml/bottle, and close by securing the dropper bottle andbottle cap.

EXAMPLE 55

The following formulation may be used for microinfusion applications offormulations containing at least one compound of the invention as anactive ingredient component.

Microinfusable Formulation

    ______________________________________                                        Active ingredient     10 mg                                                   Sodium Chloride       16 g                                                    Hydrochloric acid solution, 0.1 M                                                                   q.s. to pH 4.0 to 7.0                                   Sodium hydroxide solution, 0.1 M                                                                    q.s. to pH 4.0 to 7.0                                   Sterile water         q.s. to 20 ml                                           ______________________________________                                    

The active ingredient and sodium chloride are dissolved in most of thewater (35°-40° C.) and the pH is adjusted to between 4.0 and 7.0 usingthe hydrochloric acid or the sodium hydroxide as appropriate. The baththen is made up to volume with the water and filtered through a sterilemicropore filter into a sterile amber glass vial 20 ml and sealed withsterile closure and overseals.

EXAMPLE 56 Transdermal Administration

Compositions comprising compounds of formula (I) as an active ingredientmay be utilized in transdermal administration devices such astransdermal patches.

The patches bearing or otherwise containing the transdermal formulationare positioned on the body of a wearer in such manner as to remain incontact with the epidermis of the recipient for a prolonged period oftime.

Such patches suitably comprise the active compound (1) in an optionallybuffered, aqueous solution, (2) dissolved and/or dispersed in anadhesive, or (3) dispersed in a polymer.

A suitable concentration of the active compound is about 1% to about35%, and preferably from about 3% to about 15%.

By way of example, the active compound may be delivered from the patchby electrotransport or iontophoresis, as generally described inPharmaceutical Research, 3(6), 318 (1986).

EXAMPLE 57

A specific example of a transdermal formulation comprising a compound ofthe invention as the active ingredient is set out below.

Transdermal Formulation

    ______________________________________                                        Active ingredient      200 mg                                                 Alcohol USP            0.1 ml                                                 Hydroxyethyl cellulose                                                        ______________________________________                                    

The active ingredient and alcohol USP are gelled with hydroxyethylcellulose and packed in a transdermal device with surface area of 10cm².

While the invention has been illustratively described herein withrespect to various illustrative aspects, features and embodiments, itwill be appreciated that numerous variations, modifications and otherembodiments are possible in the practice of the present invention, andthe invention therefore is to be broadly construed as encompassing allsuch variations, modifications and other embodiments, within its spiritand scope.

We claim:
 1. A compound of the formula: ##STR34## wherein: R⁸ and R⁹ maybe the same or different, and may be:hydrogen; C₁ -C₆ alkyl; C₂ -C₆alkenyl; C₂ -C₆ alkynyl; C₂ -C₆ hydroxyalkyl; C₂ -C₆ methoxyalkyl; C₃-C₆ cycloalkyl; C₆ -C₁₀ aryl; or C₆ -C₁₀ aryl substituted with one ormore substituents selected from the group consisting of fluoro, chloro,bromo, iodo, and C₁ -C₃ alkoxy; pyridinyl; or C₆ -C₁₀ aryl C₁ -C₆ alkyl;or R⁸ and R⁹ together with the nitrogen atom to which they are bondedform a pyrrolidino or 4-methylpiperazino ring; R³, R⁴, R⁵ =hydrogen ormethyl, where the total number of methyl groups is one or two; and R⁶=hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₂ -C₆methoxyalkyl, or C₃ -C₆ cycloalkyl, or a pharmaceutically acceptablesalt thereof. 2.(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-benzyl-N-methylbenzamideor a pharmaceutically acceptable monophosphate ester or salt thereof. 3.A compound according to claim 1 wherein R⁶ is C₁ -C₆ alkyl, C₂ -C₆alkenyl, or C₃ -C₆ cycloalkyl.
 4. A compound according to claim 1,wherein R³ and R⁵ are both methyl, and R⁴ is hydrogen.
 5. A compound ofthe formula: ##STR35## wherein: R⁸ and R⁹ may be the same or different,and may be:hydrogen; C₁ -C₆ alkyl; C₂ -C₆ alkenyl; C₂ -C₆ alkynyl; C₂-C₆ hydroxyalkyl; C₂ -C₆ methoxyalkyl; C₃ -C₆ cycloalkyl; C₆ -C₁₀ aryl;or C₆ -C₁₀ aryl substituted with one or more substituents selected fromthe group consisting of fluoro, chloro, bromo, iodo, and C₁ -C₃ alkoxy;pyridinyl; or C₆ -C₁₀ aryl C₁ -C₆ alkyl; and wherein one of R⁵ and R⁹ isfluorophenyl, R³, R⁴, R⁸ =hydrogen or methyl, where the total number ofmethyl groups is one or two; and R⁶ =hydrogen, C₁ -C₆ alkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, C₂ -C₆ methoxyalkyl, or C₃ -C₆ cycloalkyl, or apharmaceutically acceptable salt thereof.
 6. A compound according toclaim 1 wherein the moiety NR⁸ R⁹ is selected from the group consistingof: ##STR36##
 7. A compound according to claim 1 wherein R⁶ is allyl. 8.A compound of the formula: ##STR37## wherein: R⁸ and R⁹ may be the sameor different, and may be:hydrogen; C₁ -C₆ alkyl; C₂ -C₆ alkenyl; C₂ -C₆alkynyl; C₂ -C₆ hydroxyalkyl; C₂ -C₆ methoxyalkyl; C₃ -C₆ cycloalkyl; C₆-C₁₀ aryl; or C₆ -C₁₀ aryl substituted with one or more substituentsselected from the group consisting of fluoro, chloro, bromo, iodo, andC₁ -C₃ alkoxy; or pyridinyl; or R⁸ and R⁹ together with the nitrogenatom to which they are bonded form a pyrrolidino or 4-methylpiperazinoring; or a pharmaceutically acceptable salt thereof.
 9. A compound ofthe formula: ##STR38## wherein: R⁸ and R⁹ may be the same or different,and may be:hydrogen; C₁ -C₆ alkyl; C₂ -C₆ alkenyl; C₂ -C₆ alkynyl; C₂-C₆ hydroxyalkyl; C₂ -C₆ methoxyalkyl; C₃ -C₆ cycloalkyl; C₆ -C₁₀ aryl;C₆ -C₁₀ aryl substituted with one or more substituents selected from thegroup consisting of fluoro, chloro, bromo, iodo, and C₁ -C₃ alkoxy; orpyridinyl; and wherein one of R⁸ and R⁹ is fluorophenyl, or apharmaceutically acceptable salt thereof.
 10. A compound selected fromthe group consisting of: ##STR39## or a pharmaceutically acceptable saltthereof.
 11. A compound selected from those of the group consistingof:(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-fluorophenyl)-N-methylbenzamide(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-phenylbenzamide(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-chlorophenyl)-N-methylbenzamide(+)-3-((α)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-phenylbenzamide(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-(2-pyridyl)benzamide(-)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-phenylbenzamide3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-(2-(trifluoromethyl)phenyl)benzamide3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-(2,4,6-trichlorophenyl)benzamide3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-(4-pyridyl)benzamide3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-(3-pyridyl)benzamide(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-benzyl-N-methylbenzamide(±)-cis-3-(α-(4-Allyl-3,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide3-((αR orαS)-α-((2S,5S)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide3-((αR orαS)-α-((2R,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-isopropyl-N-methylbenzamide(-)-3-((αR)-α-((2S,5R)-4-(Cyclopropylmethyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide(+)-3-((αR)-α-((2S,5R)-2,5-Dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide(+)-3-((αR)-α-((2S,5R)-2,5-Dimethyl-4-ethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide(-)-3-((αR)-α-((2S,5R)-2,5-Dimethyl-4-(2-propynyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide(±)-3-((αR*)-α-((2S*,5R*)-2,5-Dimethyl-4-propyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide(+)-3-((αR)-α-((2S,5R)-2,4,5-Trimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide(+)-3-((αS)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-phenylbenzamideand(+)-3-((αR)-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N-ethyl-N-(4-fluorophenyl)benzamideor a pharmaceutically acceptable salt thereof. 12.(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide.13. A pharmaceutically acceptable salt of(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide.14. A pharmaceutical composition comprising a compound of the formula:##STR40## wherein: R⁸ and R⁹ may be the same or different, and maybe:hydrogen; C₁ -C₆ alkyl; C₂ -C₆ alkenyl; C₂ -C₆ alkynyl; C₂ -C₆hydroxyalkyl; C₂ -C₆ methoxyalkyl; C₃ -C₆ cycloalkyl; C₆ -C₁₀ aryl; orC₆ -C₁₀ aryl substituted with one or more substituents selected from thegroup consisting of fluoro, chloro, bromo, iodo, and C₁ -C₃ alkoxy;pyridinyl; or C₆ -C₁₀ aryl C₁ -C₆ alkyl; or R⁸ and R⁹ together with thenitrogen atom to which they are bonded form a pyrrolidino or4-methylpiperazino ring; R³, R⁴, R⁵ =hydrogen or methyl, where the totalnumber of methyl groups is one or two; and R⁶ =hydrogen, C₁ -C₆ alkyl,C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₂ C₆ methoxyalkyl, or C₃ -C₆cycloalkyl, or a pharmaceutically acceptable salt thereof; andapharmaceutically acceptable carder therefor.
 15. A pharmaceuticalcomposition comprising: (A)(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-benzyl-N-methylbenzamideor a pharmaceutically acceptable monophosphate ester or salt thereof;and (B) a pharmaceutically acceptable carrier therefor.
 16. Apharmaceutical composition according to claims 14 or 15 in a formsuitable for injectable administration.
 17. A pharmaceutical compositionaccording to claims 14 or 15 in a form suitable for spinaladministration.
 18. A pharmaceutical composition comprising: (A)(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamideor a pharmaceutically acceptable monophosphate ester or salt thereof;and (B) a pharmaceutically acceptable carrier therefor.
 19. A method oftreating pain in an animal which comprises administering to said animalan effective amount of a compound selected from compounds of theformula: ##STR41## wherein: R⁸ and R⁹ may be the same or different, andmay be:hydrogen; C₁ -C₆ alkyl; C₂ -C₆ alkenyl; C₂ -C₆ alkynyl; C₂ -C₆hydroxyalkyl; C₂ -C₆ methoxyalkyl; C₃ -C₆ cycloalkyl; C₆ -C₁₀ aryl; orC₆ -C₁₀ aryl substituted with one or more substituents selected from thegroup consisting of fluoro, chloro, bromo, iodo, and C₁ -C₃ alkoxy;pyridinyl; or C₆ -C₁₀ aryl C₁ -C₆ alkyl; or R⁸ and R⁹ together with thenitrogen atom to which they are bonded form a pyrrolidino or4-methylpiperazino ring; R³, R⁴, R⁵ =hydrogen or methyl, where the totalnumber of methyl groups is one or two; and R⁶ =hydrogen, C₁ -C₆ alkyl,C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₂ -C₆ methoxyalkyl, or C₃ -C₆cycloalkyl, or a pharmaceutically acceptable salt thereof.
 20. A methodof treating pain in an animal which comprises administering to saidanimal an effective amount of(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-benzyl-N-methylbenzamideor a monophosphate ester or pharmaceutically acceptable salt thereof.21. A method of treating pain in a mammal which comprises administeringto said mammal an effective amount of(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piper-azinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamideor a pharmaceutically acceptable monophosphate ester or salt thereof.22. A method according to claims 20 or 21 wherein said mammal is ahuman.
 23. A method of effecting a receptor-mediated analgesia of ananimal in need of same, which comprises administering to said animal aneffective amount of a compound selected from compounds of the formula:##STR42## wherein: R⁸ and R⁹ may be the same or different, and may behydrogen, C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, C₆ -C₁₀ aryl, or C₆ -C₁₀ arylC₁ -C₆ alkyl, or R⁸ and R⁹ together with the nitrogen to which they arebonded may form a pyrrolidino or 4-methylpiperazino ring;R³, R⁴, R⁵=hydrogen or methyl, where the total number of methyl groups is one ortwo; and R⁶ =hydrogen, C₁ -C₆ alkyl, C₂ -C₆ methoxyalkyl, or C₃ -C₆cycloalkyl, or a pharmaceutically acceptable salt thereof.
 24. A methodof effecting a receptor-mediated analgesia of an animal in need of same,which comprises administering to said animal an effective amount of(+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-benzyl-N-methylbenzamideor a pharmaceutically acceptable monophosphate ester or salt thereof.